[1,2,4]triazolo[3,4-C][1,4]oxazines as P2X7 modulators

ABSTRACT

Compounds of the formula I: 
                         
or pharmaceutically acceptable salts thereof, wherein X, Y, R 1 , R 2 , and R 3  are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with the P2X7 purinergic receptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is entitled to the benefit of U.S. provisional patent application Ser. No. 61/244,322 filed on Sep. 21, 2009, the disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to compounds useful for treatment of diseases associated with P2X purinergic receptors, and more particularly to P2X₇ modulators usable for treatment of autoimmune and inflammatory diseases.

BACKGROUND OF THE INVENTION

P2X purinergic receptors are ATP-activated ionotropic receptors having seven subtypes. The P2X7 receptor subtype (also known as the P2Z receptor) is a ligand-gated ion channel found on mast cells, peripheral macrophages, lymphocytes, erythrocytes, fibroblasts and epidermal langerhans cells. Activation of P2X7 receptor on such immune system cells results in release of interleukin-1beta. (Solle et al., J. Biol. Chemistry 276, 125-132, (2001)). The P2X7 receptor is also found on microglia, Schwann cells and astrocytes within the central nervous system (Donnelly-Roberts et al., Br. J. Pharmacol. 151, 571-579 (2007)).

Antagonists of P2X7 have been shown to block P2×7-mediated IL-1beta release and P2×7-mediated cation flux (Stokes et al., Br. J. Pharmacol. 149, 880-887 (2006)). Mice lacking the P2X7 receptor show a lack of inflammatory and neuropathic hypersensitivity to mechanical and thermal stimuli (Chessell et al., Pain 114, 386-396 (2005)). P2X7 is thus believed to have a role in inflammatory responses (Ferrari et al., J. Immunol. 176, 3877-3883 (2006)) and in the onset and persistence of chronic pain (Honore et al., J. Pharmacol. Ex. Ther. 319, 1376-1385 (2006b)).

Modulators of the P2X7 receptor thus may have utility in the treatment of disease states such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, irritable bowel disease, diabetes and Crohn's disease. P2X7 modulators may also be useful for treatment of pain, including chronic pain, neuropathic pain, and pain associated inflammatory processes and degenerative conditions.

There is accordingly a need for compounds that act as modulators of P2X receptors, including antagonists of P2X7 receptor, as well as a need for methods of treating diseases, conditions and disorders mediated by P2X7. The present invention satisfies these needs as well as others.

SUMMARY OF THE INVENTION

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof, wherein:

R¹ is:

optionally substituted phenyl; or

optionally substituted heteroaryl;

R² is:

-   -   optionally substituted phenyl;     -   optionally substituted heteroaryl; or     -   optionally substituted C₃₋₆cycloalkyl;

R³ is:

-   -   hydrogen; or     -   C₁₋₆alkyl;

X is: —O—; —NR^(a)—; —S(O)_(m)— or —CR^(b)R^(c) wherein: m is from 0 to 2; R^(a) is hydrogen, C₁₋₆alkyl; or C₁₋₆alkyl-carbonyl; and R^(b) and R^(c) each independently is hydrogen or C₁₋₆alkyl; or and R^(b) and R^(c) together with the atom to which they are attached may form a carbocyclic ring that optionally includes an oxygen as a ring atom; and

Y is: —O—; —NR^(d)—; —S(O)_(n)— or —CR^(e)R^(f)— wherein n is from 0 to 2, and R^(d), R^(e) and R^(f) each independently is hydrogen or C₁₋₆alkyl.

The invention also provides and pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of preparing the compounds.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural referents unless the context clearly dictates otherwise.

“Alkyl” means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms.

“Lower alkyl” refers to an alkyl group of one to six carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.

“Alkoxy” and “alkyloxy”, which may be used interchangeably, mean a moiety of the formula —OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

“Alkoxyalkyl” means a moiety of the formula R^(a)—O—R^(b)—, where R^(a) is alkyl and R^(b) is alkylene as defined herein. Exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and 1-(2-methoxyethyl)-3-methoxypropyl.

“Alkoxyalkoxy” means a group of the formula —O—R—R′ wherein R is alkylene and R′ is alkoxy as defined herein.

“Alkylcarbonyl” means a moiety of the formula —C(O)—R, wherein R is alkyl as defined herein.

“Alkoxycarbonyl” means a group of the formula —C(O)—R wherein R is alkoxy as defined herein.

“Alkylcarbonylalkyl” means a group of the formula —R—C(O)—R wherein R is alkylene and R′ is alkyl as defined herein.

“Alkoxycarbonylalkyl” means a group of the formula —R—C(O)—R wherein R is alkylene and R′ is alkoxy as defined herein.

“Alkoxycarbonylalkoxy” means a group of the formula —O—R—C(O)—R′ wherein R is alkylene and R′ is alkoxy as defined herein.

“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OH wherein R is alkylene as defined herein.

“Alkylaminocarbonylalkoxy” means a group of the formula —O—R—C(O)—NHR′ wherein R is alkylene and R′ is alkyl as defined herein.

“Dialkylaminocarbonylalkoxy” means a group of the formula —O—R—C(O)—NR′R″ wherein R is alkylene and R′ and R″ are alkyl as defined herein.

“Alkylaminoalkoxy” means a group of the formula —O—R—NHR′ wherein R is alkylene and R′ is alkyl as defined herein.

“Dialkylaminoalkoxy” means a group of the formula —O—R—NR′R″ wherein R is alkylene and R′ and R″ are alkyl as defined herein.

“Alkylsulfonyl” means a moiety of the formula —SO₂—R, wherein R is alkyl as defined herein.

“Alkylsulfonylalkyl” means a moiety of the formula —R′—SO₂—R″ where R′ is alkylene and R″ is alkyl as defined herein.

“Alkylsulfonylalkoxy” means a group of the formula —O—R—SO₂—R′ wherein R is alkylene and R′ is alkyl as defined herein.

“Amino” means a moiety of the formula —NRR′ wherein R and R′ each independently is hydrogen or alkyl as defined herein. “Amino” thus includes “alkylamino” (where one of R and R′ is alkyl and the other is hydrogen) and “dialkylamino” (where R and R′ are both alkyl.

“Aminocarbonyl” means a group of the formula —C(O)—R wherein R is amino as defined herein.

“Alkoxyamino” means a moiety of the formula —NR—OR′ wherein R is hydrogen or alkyl and R′ is alkyl as defined herein.

“Alkylsulfanyl” means a moiety of the formula —SR wherein R is alkyl as defined herein.

“Aminoalkyl” means a group —R—R′ wherein R′ is amino and R is alkylene as defined herein. “Aminoalkyl” includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of “aminoalkyl” may be substituted once or twice with alkyl to provide “alkylaminoalkyl” and “dialkylaminoalkyl” respectively. “Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like. “Dialkylaminoalkyl” includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.

“Aminoalkoxy” means a group —OR—R′ wherein R′ is amino and R is alkylene as defined herein.

“Alkylsulfonylamido” means a moiety of the formula —NR′SO₂—R wherein R is alkyl and R′ is hydrogen or alkyl.

“Aminocarbonyloxyalkyl” or “carbamylalkyl” means a group of the formula —R—O—C(O)—NR′R″ wherein R is alkylene and R′, R″ each independently is hydrogen or alkyl as defined herein.

“Alkynylalkoxy” means a group of the formula —O—R—R′ wherein R is alkylene and R′ is alkynyl as defined herein.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof, each being optionally substituted.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean a radical-R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an aryl group as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like are examples of arylalkyl.

“Arylsulfonyl” means a group of the formula —SO₂—R wherein R is aryl as defined herein.

“Aryloxy” means a group of the formula —O—R wherein R is aryl as defined herein.

“Aralkyloxy” means a group of the formula —O—R—R″ wherein R is alkylene and R′ is aryl as defined herein.

“Carboxy” or “hydroxycarbonyl”, which may be used interchangeably, means a group of the formula —C(O)—OH.

“Cyanoalkyl” means a moiety of the formula —R′—R″, where R′ is alkylene as defined herein and R″ is cyano or nitrile.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Preferred cycloalkyl are unsubstituted or substituted with alkyl. Cycloalkyl can optionally be substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ is alkylene and R″ is cycloalkyl as defined herein.

“Cycloalkylalkoxy” means a group of the formula —O—R—R′ wherein R is alkylene and R′ is cycloalkyl as defined herein.

“Heteroalkyl” means an alkyl radical as defined herein wherein one, two or three hydrogen atoms have been replaced with a substituent independently selected from the group consisting of —OR^(a), —NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein R^(a) is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; and when n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R^(d) is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like, including partially hydrogenated derivatives thereof, each optionally substituted.

“Heteroarylalkyl” or “heteroaralkyl” means a group of the formula —R—R′ wherein R is alkylene and R′ is heteroaryl as defined herein.

“Heteroarylsulfonyl” means a group of the formula —SO₂—R wherein R is heteroaryl as defined herein.

“Heteroaryloxy” means a group of the formula —O—R wherein R is heteroaryl as defined herein.

“Heteroaralkyloxy” means a group of the formula —O—R—R″ wherein R is alkylene and R′ is heteroaryl as defined herein.

The terms “halo”, “halogen” and “halide”, which may be used interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen. Exemplary haloalkyls include —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and the like.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkyl moiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.

“Heterocycloamino” means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.

“Heterocyclylalkyl” means a moiety of the formula —R—R′ wherein R is alkylene and R′ is heterocyclyl as defined herein.

“Heterocyclyloxy” means a moiety of the formula —OR wherein R is heterocyclyl as defined herein.

“Heterocyclylalkoxy” means a moiety of the formula —OR—R′ wherein R is alkylene and R′ is heterocyclyl as defined herein.

“Hydroxyalkoxy” means a moiety of the formula —OR wherein R is hydroxyalkyl as defined herein. Exemplary hydroxyalkoxy include, for example, 3-methoxy-2-hydroxy-propyl and 3-hydroxy-2-methoxy-propyl.

“Hydroxyalkoxyalkyl” means a moiety of the formula —ROR′ wherein R is alkylene and R′ is hydroxyalkyl as defined herein, and R or R′ or both are substituted with hydroxy.

“Hydroxyalkylamino” means a moiety of the formula —NR—R′ wherein R is hydrogen or alkyl and R′ is hydroxyalkyl as defined herein.

“Hydroxyalkylaminoalkyl” means a moiety of the formula —R—NR′—R″ wherein R is alkylene, R′ is hydrogen or alkyl, and R″ is hydroxyalkyl as defined herein.

“Hydroxycarbonylalkyl” or “carboxyalkyl” means a group of the formula —R—(CO)—OH where R is alkylene as defined herein.

“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OH wherein R is alkylene as defined herein.

“Hydroxyalkyloxycarbonylalkyl” or “hydroxyalkoxycarbonylalkyl” means a group of the formula —R—C(O)—O—R—OH wherein each R is alkylene and may be the same or different.

“Hydroxyalkyl” means an alkyl moiety as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl

“Hydroxycycloalkyl” means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

“Alkoxy hydroxyalkyl” and “hydroxy alkoxyalkyl”, which may be used interchangeably, means an alkyl as defined herein that is substituted at least once with hydroxy and at least once with alkoxy. “Alkoxy hydroxyalkyl” and “hydroxy alkoxyalkyl” thus encompass, for example, 2-hydroxy-3-methoxy-propan-1-yl and the like.

“Urea” or “ureido” means a group of the formula —NR′—C(O)—NR″R′″ wherein R′, R″ and R′″ each independently is hydrogen or alkyl.

“Carbamate” means a group of the formula —O—C(O)—NR′R″ wherein R′ and R″ each independently is hydrogen or alkyl.

“Carboxy” means a group of the formula —O—C(O)—OH.

“Sulfonamido” means a group of the formula —SO₂—NR′R″ wherein R′, R″ and R′″ each independently is hydrogen or alkyl.

“Optionally substituted”, when used in association with “aryl”, “phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl”, means an aryl, phenyl, heteroaryl, cycloalkyl or heterocyclyl which is optionally substituted independently with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, dialkylamino, haloalkyl, haloalkoxy, heteroalkyl, —COR, —SO₂R (where R is hydrogen, alkyl, phenyl or phenylalkyl), —(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′ and R″ are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or —(CR′R″)_(n)—CONR^(a)R^(b) (where n is an integer from 0 to 5, R′ and R″ are independently hydrogen or alkyl, and R^(a) and R^(b) are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). Certain preferred optional substituents for “aryl”, “phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl” include alkyl, halo, haloalkyl, alkoxy, cyano, amino and alkylsulfonyl. More preferred substituents are methyl, fluoro, chloro, trifluoromethyl, methoxy, amino and methanesulfonyl.

“Leaving group” means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.

“Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

“Disease” and “Disease state” means any disease, condition, symptom, disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include:

acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or

salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

The preferred pharmaceutically acceptable salts are the salts formed from acetic acid, hydrochloric acid, sulphuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium.

It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.

“Protective group” or “protecting group” means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms “amino-protecting group” and “nitrogen protecting group” are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. The artisan in the art will know how to chose a group for the ease of removal and for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H₂O, such combination being able to form one or more hydrate.

“Subject” means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term “subject” does not denote a particular age or sex.

“Arthritis” means diseases or conditions damage to joints of the body and pain associated with such joint damage. Arthritis includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis and gouty arthritis.

“Pain” includes, without limitation, inflammatory pain; surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve injury; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.

“Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

The terms “those defined above” and “those defined herein” when referring to a variable incorporates by reference the broad definition of the variable as well as preferred, more preferred and most preferred definitions, if any.

“Treating” or “treatment” of a disease state includes:

-   -   (i) preventing the disease state, i.e. causing the clinical         symptoms of the disease state not to develop in a subject that         may be exposed to or predisposed to the disease state, but does         not yet experience or display symptoms of the disease state.     -   (ii) inhibiting the disease state, i.e., arresting the         development of the disease state or its clinical symptoms, or     -   (iii) relieving the disease state, i.e., causing temporary or         permanent regression of the disease state or its clinical         symptoms.

The terms “treating”, “contacting” and “reacting” when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.

Nomenclature and Structures

In general, the nomenclature used in this application is based on AUTONOM™ v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. Chemical structures shown herein were prepared using ISIS® version 2.2. Any open valency appearing on a carbon, oxygen sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom unless indicated otherwise. Where a nitrogen-containing heteroaryl ring is shown with an open valency on a nitrogen atom, and variables such as R^(a), R^(b) or R^(c) are shown on the heteroaryl ring, such variables may be bound or joined to the open valency nitrogen. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. Where a structure shown herein may exist in multiple tautomeric forms, all such tautomers are encompassed by the structure.

All patents and publications identified herein are incorporated herein by reference in their entirety.

Compounds of the Invention

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof, wherein:

R¹ is:

optionally substituted phenyl; or

optionally substituted heteroaryl;

R² is:

-   -   optionally substituted phenyl;     -   optionally substituted heteroaryl; or     -   optionally substituted C₃₋₆cycloalkyl;

R³ is:

-   -   hydrogen; or     -   C₁₋₆alkyl;

X is: —O—; —NR^(a)—; —S(O)_(m)— or —CR^(b)R^(c) wherein: m is from 0 to 2; R^(a) is hydrogen, C₁₋₆alkyl; or C₁₋₆alkyl-carbonyl; and R^(b) and R^(c) each independently is hydrogen or C₁₋₆alkyl; or and R^(b) and R^(c) together with the atom to which they are attached may form a carbocyclic ring that optionally includes oxygen as a ring atom; and

Y is: —O—; —NR^(d)—; —S(O)_(n)— or —CR^(e)R^(f)— wherein n is from 0 to 2, and R^(d), R^(e) and R^(f) each independently is hydrogen or C₁₋₆alkyl.

In certain embodiments of formula I, R³ is hydrogen.

In certain embodiments of formula I, R³ is C₁₋₆alkyl.

In certain embodiments of formula I, R³ is methyl.

In certain embodiments of formula I, R¹ is substituted phenyl.

In certain embodiments of formula I, R¹ is phenyl substituted one, two, three or four times, and preferably substituted one, two or three times, with a substituent or substituents each independently selected from: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfanyl; C₁₋₆alkylsulfinyl; phenylsulfonyl wherein the phenyl portion is optionally substituted with C₁₋₆alkyl; nitrile; hydroxy; C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkoxycarbonyl; C₁₋₆alkoxycarbonyl-C₁₋₆alkoxy; hydroxycarbonyl; hydroxycarbonyl-C₁₋₆alkoxy; C₁₋₆alkylaminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylamino-C₁₋₆alkoxy; C₁₋₆alkylsulfony-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkoxy; amino; amino-C₁₋₆alkyl; C₁₋₆alkenyl; C₁₋₆alkynyl; morpholinyl; morpholinyl-C₁₋₆alkyl; piperazinyl; piperidinyloxy; aminocarbonyl-C₁₋₆alkoxy; hydroxy C₁₋₆alkoxy-C₁₋₆alkyl; C₁₋₆alkoxyamino-C₁₋₆alkyl; hydroxy-C₁₋₆alkylamino-C₁₋₆alkyl; C₁₋₆alkoxycarbonylamino-C₁₋₆alkyl; C₁₋₆alkylcarbonylamino-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl; C₁₋₆alkoxycarbonyl-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl; C₁₋₆alkylamino-C₁₋₆alkyl; hydroxycarbonyl-C₁₋₆alkyl; or nitro; a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted; or two adjacent substituents may form a C₁₋₂alkylenedioxy or halo-C₁₋₂alkylenedioxy.

In embodiments of formula I wherein R¹ is phenyl substituted once or twice with C₁₋₆alkyl, C₁₋₆alkoxy or halo, and once with a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl; such heteroaryl may be optionally substituted once or twice with a group or groups independently selected from: C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl; halo, halo-C₁₋₆alkyl; hydroxy-C₁₋₆alkoxy; C₁₋₆alkoxy-C₁₋₆alkoxy; or oxo.

In embodiments of formula I wherein R¹ is phenyl substituted once or twice with C₁₋₆alkyl, C₁₋₆alkoxy or halo, and once with a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl; such heteroaryl may be optionally substituted once or twice with a group or groups independently selected from: C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl; halo, halo-C₁₋₆alkyl; or oxo.

In embodiments of formula I wherein R¹ is phenyl substituted once or twice with C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy-C₁₋₆alkoxy or halo, and once with a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl; such heteroaryl may be optionally substituted once or twice with a group or groups independently selected from: C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; halo, or oxo.

In embodiments of formula I wherein R¹ is phenyl substituted once or twice with C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy-C₁₋₆alkoxy or halo, and once with a five- or six-membered heteroaryl selected from pyrazolyl and pyridazinyl, each optionally substituted once or twice with a group or groups independently selected from: C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; halo, or oxo.

In certain embodiments of formula I, R¹ is phenyl substituted one, two, three or four times, and preferably substituted one, two or three times, with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; trifluoromethoxy; methanesulfonyl; methanesulfanyl; methanesulfinyl; toluenesulfonyl; nitrile; acetyl; aminocarbonyl; methoxycarbonyl; methoxycarbonylmethoxy; carboxy; hydroxycarbonylmethoxy; methylaminocarbonylmethoxy; methoxyethoxy; hydroxyethoxy; methylaminoethoxy; methanesulfonylpropyloxy; hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; amino; or nitro; morpholinyl; N,N-dimethylaminocarbonylmethoxy; boc-piperazinyl; N-(2-methoxyethyl)-N-methylaminomethyl; N,N-dimethylaminomethyl; aminomethyl; boc-aminomethyl; methylcarbonylaminomethyl; N,N-di-(2-hydroxyethyl)-aminomethyl; morpholinylmethyl; 2-hydroxy-1-hydroxymethyl-ethyl; methylaminocarbonyl; piperidinyloxy; tert-butoxycarbonylmethyl; N,N-dimethylaminocarbonylmethyl; n-propyl; isopropyl; hydroxycarbonylmethyl; hydroxypropoxy; a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted; or two adjacent substituents may form methylenedioxy, ethylenedioxy or difluoromethylenedioxy.

In certain embodiments of formula I, R¹ is phenyl substituted one, two, three or four times, and preferably substituted one, two or three times, with a substituent or substituents each independently selected from: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; nitrile; C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkylamino; C₁₋₂alkylenedioxy; C₃₋₆cycloalkyl-C₁₋₆alkoxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted.

In certain embodiments of formula I, R¹ is phenyl substituted one, two, three or four times, and preferably substituted one, two or three times, with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylenedioxy; ethylenedioxy; pyrrol-1-yl; 2-hydroxy-5-methyl-pyrazol-3-yl; 2-methyl-tetrazol-5-yl; 1,5-dimethyl-pyrazol-3-yl; pyrazol-3-yl; 5-methyl-pyridin-2-yl; 1-(2-hydroxy-propyl)-5-methyl-pyrazol-3-yl; 2-isobutyl-pyrazol-3-yl; 1-methyl-tetrazol-5-yl; 6-methyl-pyridin-3-yl; pyrazol-1-yl; 2-methyl-pyrazol-3-yl; 5-ethyl-pyrazol-3-yl; 4,5-dimethyl-pyrazol-3-yl; 3,5-dioxo-4-5-dihydro[1,2,4]triazin-2-yl; 5-ethyl-1H-pyrazol-3-yl; 1,5-dimethyl-1H-pyrazol-3-yl; 1-((R)-2,3-dihydroxy-propyl)-5-methyl-1H-pyrazol-3-yl; 2,5-dimethyl-2H-pyrazol-3-yl; 5-methyl-1H-[1,2,4]triazol-3-yl; 1,5-dimethyl-1H-[1,2,4]triazol-3-yl; 3-methyl-isoxazol-5-yl; 3-methyl-[1,2,4]triazol-1-yl; 4-methyl-[1,2,3]triazol-1-yl; 4-methyl-pyrazol-1-yl; 5-methyl-[1,3,4]oxadiazol-2-yl; 2-propyl-pyrazol-3-yl; 4,5-dimethyl-[1,2,4]triazol-3-yl; 2-oxo-oxazolidin-3-ylmethyl; 4-methyl-3,5-dioxo-4,5-dihydro-[1,2,4]triazin-2-yl; 5-methyl-pyrazol-3-yl; 4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-[1,2,4]triazin-2-yl; or 5-methyl-isoxazol-3-yl.

In certain embodiments of formula I, R¹ is phenyl substituted one, two, three or four times, and preferably substituted one, two or three times, with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylenedioxy; ethylenedioxy; pyrrol-1-yl; 2-hydroxy-5-methyl-pyrazol-3-yl; 2-methyl-tetrazol-5-yl; 1,5-dimethyl-pyrazol-3-yl; pyrazol-3-yl; 5-methyl-pyridin-2-yl; 1-(2-hydroxy-propyl)-5-methyl-pyrazol-3-yl; 2-isobutyl-pyrazol-3-yl; 1-methyl-tetrazol-5-yl; 6-methyl-pyridin-3-yl; pyrazol-1-yl; 2-methyl-pyrazol-3-yl; 5-ethyl-pyrazol-3-yl; 4,5-dimethyl-pyrazol-3-yl; 3,5-dioxo-4-5-dihydro[1,2,4]triazin-2-yl; 5-ethyl-1H-pyrazol-3-yl; 1,5-dimethyl-1H-pyrazol-3-yl; 1-((R)-2,3-dihydroxy-propyl)-5-methyl-1H-pyrazol-3-yl; 2,5-dimethyl-2H-pyrazol-3-yl; 5-methyl-1H-[1,2,4]triazol-3-yl; 1,5-dimethyl-1H-[1,2,4]triazol-3-yl; 3-methyl-isoxazol-5-yl; 3-methyl-[1,2,4]triazol-1-yl; 4-methyl-[1,2,3]triazol-1-yl; 4-methyl-pyrazol-1-yl; 5-methyl-[1,3,4]oxadiazol-2-yl; 2-propyl-pyrazol-3-yl; 4,5-dimethyl-[1,2,4]triazol-3-yl; 2-oxo-oxazolidin-3-ylmethyl; 4-methyl-3,5-dioxo-4,5-dihydro-[1,2,4]triazin-2-yl; 5-methyl-pyrazol-3-yl; 4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-[1,2,4]triazin-2-yl; or 5-methyl-isoxazol-3-yl.

In certain embodiments of formula I, R¹ is phenyl substituted one, two, three or four times, and preferably substituted one, two or three times, with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; 5-methyl-1H-pyrazol-3-yl; 4-methyl-pyrazol-1-yl; 5-methyl-1-(2-hydroxy-ethyl)-pyrazol-3-yl; 5-methyl-1-(2-hydroxy-propyl)-pyrazol-3-yl; 5-methyl-1-(1,2-dihydroxy-propyl)-pyrazol-3-yl; 5-methyl-1-(3-methoxy-2-hydroxy-propyl)-pyrazol-3-yl; 3-oxo-2-methyl-2H-pyridazin-4-yl; or 3-oxo-2H-pyridazin-5-yl.

In certain embodiments of formula I, R¹ is phenyl substituted at the two position with halo or C₁₋₆alkyl, and substituted one or two additional times with a substituent or substituents each independently selected from: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; nitrile; C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkylamino; C₁₋₂alkylenedioxy; or C₃₋₆cycloalkyl-C₁₋₆alkoxy.

In certain embodiments of formula I, R¹ is phenyl substituted at the two position with halo or C₁₋₆alkyl, and substituted one or two additional times with a substituent or substituents each independently selected from: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; nitrile; C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkylamino; C₁₋₂alkylenedioxy; C₃₋₆cycloalkyl-C₁₋₆alkoxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl; such heteroaryl may be optionally substituted once or twice with a group or groups independently selected from: C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; and oxo.

In certain embodiments of formula I, R¹ is phenyl substituted at the two position with C₁₋₆alkyl or halo, and substituted one or two additional times with a substituent or substituents each independently selected from: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; nitrile; C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkylamino; C₁₋₂alkylenedioxy; or C₃₋₆cycloalkyl-C₁₋₆alkoxy, or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl; such heteroaryl may be optionally substituted once or twice with a group or groups independently selected from: C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; and oxo.

In certain embodiments of formula I, R¹ is phenyl that is:

substituted at the two position with methyl or halo;

optionally substituted at the 3-position with halo or C₁₋₆alkoxy; and

substituted at the 4-position with C₁₋₆alkoxy, hydroxy-C₁₋₆alkoxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl; such heteroaryl may be optionally substituted once or twice with a group or groups independently selected from: C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; and oxo.

In certain embodiments of formula I, R¹ is phenyl that is:

substituted at the two position with methyl or halo;

optionally substituted at the 3-position with halo or C₁₋₆alkoxy; and

substituted at the 4-position with C₁₋₆alkoxy, hydroxy-C₁₋₆alkoxy; 5-methyl-1H-pyrazol-3-yl; 4-methyl-pyrazol-1-yl; 5-methyl-1-(2-hydroxy-ethyl)-pyrazol-3-yl; 5-methyl-1-(2-hydroxy-propyl)-pyrazol-3-yl; 5-methyl-1-(1,2-dihydroxy-propyl)-pyrazol-3-yl; 5-methyl-1-(3-methoxy-2-hydroxy-propyl)-pyrazol-3-yl; 3-oxo-2-methyl-2H-pyridazin-4-yl; or 3-oxo-2H-pyridazin-5-yl.

In certain embodiments of formula I, R¹ is phenyl substituted two or three times with substituents each independently selected from: fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; difluoromethoxy; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylenedioxy; or ethylenedioxy.

In certain embodiments of formula I, R¹ is phenyl substituted two or three times with substituents each independently selected from: fluoro; chloro; bromo; methyl; and methoxy.

In certain embodiments of formula I, R¹ is phenyl optionally substituted one, two or three times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.

In certain embodiments of formula I, R¹ is phenyl substituted at the two position with C₁₋₆alkyl or halo, and additionally substituted one or two times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; difluoromethoxy; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylenedioxy; or ethylenedioxy.

In certain embodiments of formula I, R¹ is phenyl substituted at the two position with methyl, and additionally substituted one or two times times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; difluoromethoxy; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylenedioxy; or ethylenedioxy.

In certain embodiments of formula I, R¹ is: 2-bromo-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methoxy-phenyl; 2-bromo-4-fluoro-5-methoxy-phenyl; 2,4-dichloro-5-methoxy-phenyl; 2-bromo-5-methoxy-4-trifluoromethyl-phenyl; 2-bromo-4,5-dichloro-phenyl; 2-bromo-4-chloro-5-iodo-phenyl; 2-bromo-4-chloro-5-trifluoromethyl-phenyl; 2-bromo-5-methoxy-4-methyl-phenyl; 2-isopropyl-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methanesulfanyl-phenyl; 2-bromo-4-chloro-5-methanesulfonyl-phenyl; 2-bromo-4-chloro-5-methanesulfinyl-phenyl; 2-bromo-4-chloro-5-fluoro-phenyl; 2-bromo-5-methoxy-phenyl; 2-bromo-5-methoxy-4-methoxycarbonyl-phenyl; 2-bromo-4-chloro-5-hydroxy-phenyl; 2-bromo-4-chloro-5-(methylamino-carbonyl-methyoxy)-phenyl; 2-methyl-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methoxycarbonyl-phenyl; 2-bromo-4-methanesulfonyl-5-methoxy-phenyl; 2-bromo-4-methyl-5-methoxy-phenyl; 2-bromo-4-chloro-5-(methoxycarbonyl-methoxy)-phenyl; 2-bromo-4-chloro-5-(hydroxycarbonyl-methoxy)-phenyl; 2-bromo-4-chloro-5-(2-methoxyethoxy)-phenyl; 4,5-dimethoxy-phenyl; 2-fluoro-4-chloro-5-methoxy-phenyl; 2-bromo-4-methoxycarbonyl-5-methoxy-phenyl; 6-bromo-benzo[1,3]dioxol-5-yl; 2-bromo-4-chloro-5-(2-hydroxyethoxy)-phenyl; 2-bromo-4-difluoromethoxy-5-methoxy-phenyl; 5-methoxy-4-methyl-phenyl; 2-bromo-4-chloro-5-(2-methylamino-ethoxy)-phenyl; 2-bromo-4-cyano-5-methyl-phenyl; 2-fluoro-4-methyl-5-methoxy-phenyl; 2-bromo-4-chloro-5-acetyl-phenyl; 5-methoxy-2-methyl-phenyl; 2-bromo-4-chloro-5-(3-methanesulfonyl-propoxy)-phenyl; 2-bromo-5-methoxy-4-(tert-butoxycarbonyl)-phenyl; 5-methanesulfonyl-2-methoxy-phenyl; 2-bromo-4-chloro-5-(1-hydroxyethyl)-phenyl; 2-fluoro-5-(2-hydroxyethoxy)-4-methyl-phenyl; 2-bromo-5-methoxy-4-aminocarbonyl-phenyl; 6-bromo-2,2-difluoro-benzo[1,3]dioxol-5-yl; 2,6-difluoro-phenyl; 2-bromo-4-cyano-5-methoxy-phenyl; 2,5-dimethoxy-phenyl; 3-methoxycarbonyl-2-methyl-phenyl; 3-methoxy-phenyl; 4-methoxy-phenyl; 2,4-dimethoxy-phenyl; 4-chloro-5-methoxy-phenyl; 4-fluoro-5-methoxy-phenyl; 2-bromo-4-methyl-5-(tert-butoxycarbonyl)-phenyl; 3,4,5-trimethoxy-phenyl; 2-bromo-4,6-difluoro-phenyl; 2-ethyl-4,5-dimethoxy-phenyl; 2-bromo-4-methoxy-phenyl; 4-chloro-5-(2-hydroxyethoxy)-2-methyl-phenyl; 3-methoxycarbonyl-2-methyl-phenyl; 2,5-dimethyl-phenyl; 2-bromo-5-methoxy-phenyl; 2,3-dimethyl-phenyl; 2-bromo-4-chloro-5-hydroxymethyl-phenyl; 2-bromo-3,5-dimethyl-phenyl; 4-methoxy-2-methyl-phenyl; 2,4-dimethyl-phenyl; 2-iodo-4,5-dimethoxy-phenyl; 2-chloro-4,5-dimethoxy-phenyl; 7-bromo-2,3-dihydrobenzo[1,4]dioxin-6-yl; 4,5-dimethoxy-2-trifluoromethyl-phenyl; 2-bromo-5-ethoxy-4-methoxy-phenyl; 2-bromo-4-ethoxy-5-methoxy-phenyl; 2-bromo-5-cyclopropylmethoxy-4-methoxy-phenyl; 2-bromo-4-cyclopropylmethoxy-5-methoxy-phenyl; 2-cyano-4,5-dimethoxyphenyl; 2-bromo-5-difluoromethoxy-4-methoxy-phenyl; 2-bromo-4,5-bis-difluoromethoxy-phenyl; 2-bromo-4-fluoro-5-(2-methoxyethoxy)-phenyl; 2-bromo-4-fluoro-5-(2-hydroxyethoxy)-phenyl; 4-fluoro-4,5-dimethoxy-phenyl; 2,4-dimethylphenyl; 3,5-dimethylphenyl; 4,5-dimethoxy-2-morpholin-4-yl-phenyl; 3-methoxy-2-methyl-phenyl; 2,3-dimethoxy-phenyl; 4-fluoro-5-(2-hydroxy-ethoxy)-2-methyl-phenyl; 4-chloro-4-(3-hydroxy-propyl)-2-methyl-phenyl; 2-dimethylamino-4,5-dimethoxy-phenyl; 4-chloro-5-hydroxymethyl-2-methyl-phenyl; 2-bromo-4-trifluoromethoxy-phenyl; 2-bromo-4-chloro-5-dimethylaminocarbonylmethoxy-phenyl; 4-chloro-5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-2-methyl-phenyl; 5-(tert-butoxycarbonylaminomethyl)-2-methyl-4-chloro-phenyl; 5-aminomethyl-4-chloro-2-methyl-phenyl; 4-chloro-2-methyl-5-(methylcarbonylaminomethyl)-phenyl; 5-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-4-chloro-2-methyl-phenyl; 4-chloro-2-methyl-5-morpholin-4-ylmethyl-phenyl; 3-methyl-phenyl; 4-chloro-5-(2-hydroxy-ethyl)-2-methyl-phenyl; 2-bromo-3,4-ethylenedioxy-phenyl (7-bromo-2,3-dihydro-benzo[1,4]dioxin-6-yl)); 3-chloro-2-methyl-phenyl; 3-hydroxymethyl-2-methyl-phenyl; 2-methyl-3-methylaminocarbonyl-phenyl; 4-chloro-2-methyl-5-(piperidin-4-yloxy)-phenyl; 2-methyl-3-(tert-butoxycarbonylmethyl)-phenyl; 3-(2-hydroxy-ethyl)-2-methyl-phenyl; 4,5-difluoro-2-methyl-phenyl; 2-bromo-4,5-difluoro-phenyl; 3,4-dimethyl-phenyl; 2-chloro-3-methyl-phenyl; 2-bromo-4-(2-hydroxy-ethyl)-phenyl; 2-bromo-4-isopropyl-phenyl; 3-fluoro-2-methyl-phenyl; 2-bromo-5-(2-hydroxy-ethoxy)-4-methyl-phenyl; 2-(2-hydroxy-ethyl)-4,5-dimethoxy-phenyl; 4-chloro-5-dimethylaminomethyl-2-methyl-phenyl; 2-ethyl-phenyl; 2-propyl-phenyl; 5-methoxy-2,3-dimethyl-phenyl; and 3-(hydroxycarbonylmethyl)-2-methyl-phenyl.

In certain embodiments of formula I, R¹ is: 2-bromo-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methoxy-phenyl; 2-bromo-4-fluoro-5-methoxy-phenyl; 2,4-dichloro-5-methoxy-phenyl; 2-bromo-5-methoxy-4-trifluoromethyl-phenyl; 2-bromo-4,5-dichloro-phenyl; 2-bromo-4-chloro-5-iodo-phenyl; 2-bromo-4-chloro-5-trifluoromethyl-phenyl; 2-bromo-5-methoxy-4-methyl-phenyl; 2-isopropyl-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methanesulfanyl-phenyl; 2-bromo-4-chloro-5-methanesulfonyl-phenyl; 2-bromo-4-chloro-5-methanesulfinyl-phenyl; 2-bromo-4-chloro-5-fluoro-phenyl; 2-bromo-5-methoxy-phenyl; 2-bromo-5-methoxy-4-methoxycarbonyl-phenyl; 2-bromo-4-chloro-5-hydroxy-phenyl; 2-bromo-4-chloro-5-(methylamino-carbonyl-methyoxy)-phenyl; 2-methyl-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methoxycarbonyl-phenyl; 2-bromo-4-methanesulfonyl-5-methoxy-phenyl; 2-bromo-4-methyl-5-methoxy-phenyl; 2-bromo-4-chloro-5-(methoxycarbonyl-methoxy)-phenyl; 2-bromo-4-chloro-5-(hydroxycarbonyl-methoxy)-phenyl; 2-bromo-4-chloro-5-(2-methoxyethoxy)-phenyl; 4,5-dimethoxy-phenyl; 2-fluoro-4-chloro-5-methoxy-phenyl; 2-bromo-4-methoxycarbonyl-5-methoxy-phenyl; 6-bromo-benzo[1,3]dioxol-5-yl; 2-bromo-4-chloro-5-(2-hydroxyethoxy)-phenyl; 2-bromo-4-difluoromethoxy-5-methoxy-phenyl; 5-methoxy-4-methyl-phenyl; 2-bromo-4-chloro-5-(2-methylamino-ethoxy)-phenyl; 2-bromo-4-cyano-5-methyl-phenyl; 2-fluoro-4-methyl-5-methoxy-phenyl; 2-bromo-4-chloro-5-acetyl-phenyl; 5-methoxy-2-methyl-phenyl; 2-bromo-4-chloro-5-(3-methanesulfonyl-propoxy)-phenyl; 2-bromo-5-methoxy-4-(tert-butoxycarbonyl)-phenyl; 5-methanesulfonyl-2-methoxy-phenyl; 2-bromo-4-chloro-5-(1-hydroxyethyl)-phenyl; 2-fluoro-5-(2-hydroxyethoxy)-4-methyl-phenyl; 2-bromo-5-methoxy-4-aminocarbonyl-phenyl; 6-bromo-2,2-difluoro-benzo[1,3]dioxol-5-yl; 2,6-difluoro-phenyl; 2-bromo-4-cyano-5-methoxy-phenyl; 2,5-dimethoxy-phenyl; 3-methoxycarbonyl-2-methyl-phenyl; 3-methoxy-phenyl; 4-methoxy-phenyl; 2,4-dimethoxy-phenyl; 4-chloro-5-methoxy-phenyl; 4-fluoro-5-methoxy-phenyl; 2-bromo-4-methyl-5-(tert-butoxycarbonyl)-phenyl; 3,4,5-trimethoxy-phenyl; 2-bromo-4,6-difluoro-phenyl; 2-ethyl-4,5-dimethoxy-phenyl; 2-bromo-4-methoxy-phenyl; 4-chloro-5-(2-hydroxyethoxy)-2-methyl-phenyl; 3-methoxycarbonyl-2-methyl-phenyl; 2,5-dimethyl-phenyl; 2-bromo-5-methoxy-phenyl; 2,3-dimethyl-phenyl; 2-bromo-4-chloro-5-hydroxymethyl-phenyl; 2-bromo-3,5-dimethyl-phenyl; 4-methoxy-2-methyl-phenyl; or 2,4-dimethyl-phenyl.

In certain embodiments of formula I, R¹ is: 2-bromo-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methoxy-phenyl; 2-bromo-4-fluoro-5-methoxy-phenyl; 2-bromo-5-methoxy-4-methyl-phenyl; 2-methyl-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-(2-methoxy-ethyl-phenyl; 2-bromo-4-chloro-5-(2-hydroxy-ethyl-phenyl; 2-bromo-4-difluoromethoxy-5-methoxy-phenyl; 2,5-dimethoxy-phenyl; 2-ethyl-4,5-dimethoxy-phenyl; 2-methyl-5-(2-hydroxy-ethoxy)-4-chloro-phenyl; 2,5-dimethyl-phenyl; 2-bromo-5-methoxy-phenyl; or 2-bromo-4,5-dimethyl-phenyl.

In certain embodiments of formula I, R¹ is: 2-bromo-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methoxy-phenyl; 2-bromo-4-fluoro-5-methoxy-phenyl; 2-bromo-5-methoxy-4-methyl-phenyl; 4,5-dimethoxy-2-methyl-phenyl; 2-bromo-4,5-methylenedioxy-phenyl (6-bromo-benzo[1,3]dioxol-5-yl); 2-bromo-4-chloro-5-(2-hydroxy-ethoxy)-phenyl; 2-bromo-4-difluoromethoxy-5-methoxy-phenyl; 5-methoxy-2-methyl-phenyl; 2-bromo-4-chloro-5-(1-hydroxy-ethyl)-phenyl; 2-bromo-4-chloro-5-((S)-1-hydroxy-ethyl)-phenyl; 2-ethyl-4,5-dimethoxy-phenyl; 2-bromo-4-methoxy-phenyl; 4-chloro-5-(2-hydroxy-ethoxy)-2-methyl-phenyl; 2,5-dimethyl-phenyl; 2-bromo-5-methoxy-phenyl; 2,3-dimethyl-phenyl; 2-bromo-4-chloro-5-hydroxymethyl-phenyl; 2-bromo-3,5-dimethyl-phenyl; 2,4-dimethyl-phenyl; 3-methoxy-2-methyl-phenyl; 4-fluoro-5-(2-hydroxy-ethoxy)-2-methyl-phenyl; 4-chloro-5-(3-hydroxy-propoxy)-2-methyl-phenyl; 4-chloro-5-hydroxymethyl-2-methyl-phenyl; 5-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-4-chloro-2-methyl-phenyl; 4-chloro-5-(2-hydroxy-ethyl)-2-methyl-phenyl; 2-bromo-4,5-ethylenedioxy-phenyl (7-bromo-2,3-dihydro-benzo[1,4]dioxin-6-yl); 3-chloro-2-methyl-phenyl; 3-hydroxymethyl-2-methyl-phenyl; or 3-(2-hydroxy-ethyl)-2-methyl-phenyl.

In certain embodiments of formula I, R¹ is: 2-bromo-4,5-dimethoxy-phenyl; 4,5-dimethoxy-2-methyl-phenyl; 4-chloro-5-(2-hydroxy-ethoxy)-2-methyl-phenyl; 2-methyl-5-(5-methyl-1H-pyrazol-3-yl)-phenyl; 2-methyl-5-(4-methyl-pyrazol-1-yl)-phenyl; 2-methyl-5-[5-methyl-1-(2-hydroxy-ethyl)-pyrazol-3-yl]-phenyl; 2-methyl-5-[5-methyl-1-(2-hydroxy-propyl)-pyrazol-3-yl]-phenyl; 2-methyl-5-[5-methyl-1-(1,2-dihydroxy-propyl)-pyrazol-3-yl]-phenyl; 2-methyl-5-[5-methyl-1-(3-methoxy-2-hydroxy-propyl)-pyrazol-3-yl]-phenyl; 2-methyl-5-(6-oxo-1-methyl-pyridazin-5-yl)-phenyl; 2-chloro-5-[5-methyl-1-(2-hydroxy-ethyl)-pyrazol-3-yl]-phenyl; 2-methyl-5-(6-oxo-1H-pyridazin-3-yl)-phenyl; 2-methyl-5-(6-oxo-1H-pyridazin-5-yl)-phenyl, or 2-methyl-4-[4-((R)-2-hydroxy-3-methoxy-propyl)-2H-[1,2,4]triazine-3,5-dione]-yl-phenyl.

In certain embodiments of formula I, R¹ is 4-chloro-5-(2-hydroxy-ethoxy)-2-methyl-phenyl.

In certain embodiments of formula I, R¹ is 2-methyl-5-(5-methyl-1H-pyrazol-3-yl)-phenyl.

In certain embodiments of formula I, R¹ is 2-methyl-5-(4-methyl-pyrazol-1-yl)-phenyl.

In certain embodiments of formula I, R¹ is 2-methyl-5-[5-methyl-1-(2-hydroxy-ethyl)-pyrazol-3-yl]-phenyl.

In certain embodiments of formula I, R¹ is 2-methyl-5-[5-methyl-1-(2-hydroxy-propyl)-pyrazol-3-yl]-phenyl.

In certain embodiments of formula I, R¹ is 2-methyl-5-[5-methyl-1-(1,2-dihydroxy-propyl)-pyrazol-3-yl]-phenyl.

In certain embodiments of formula I, R¹ is 2-methyl-5-[5-methyl-1-(3-methoxy-2-hydroxy-propyl)-pyrazol-3-yl]-phenyl.

In certain embodiments of formula I, R¹ is 2-methyl-5-(6-oxo-1-methyl-pyridazin-5-yl)-phenyl.

In certain embodiments of formula I, R¹ is 2-chloro-5-[5-methyl-1-(2-hydroxy-ethyl)-pyrazol-3-yl]-phenyl.

In certain embodiments of formula I, R¹ is 2-methyl-5-(6-oxo-1H-pyridazin-3-yl)-phenyl.

In certain embodiments of formula I, R¹ is 2-methyl-5-(6-oxo-1H-pyridazin-5-yl)-phenyl.

In certain embodiments of formula I, R¹ is 2-bromo-4,5-dimethoxy-phenyl.

In certain embodiments of formula I, R¹ is 2-bromo-4-chloro-5-methoxy-phenyl.

In certain embodiments of formula I, R¹ is 2-bromo-4-fluoro-5-methoxy-phenyl.

In certain embodiments of formula I, R¹ is 2-bromo-5-methoxy-4-methyl-phenyl.

In certain embodiments of formula I, R¹ is 2-methyl-4,5-dimethoxy-phenyl.

In certain embodiments of formula I, R¹ is 2-bromo-4-chloro-5-(2-methoxy-ethyl-phenyl.

In certain embodiments of formula I, R¹ is 2-bromo-4-chloro-5-(2-hydroxy-ethyl-phenyl.

In certain embodiments of formula I, R¹ is 2-bromo-4-difluoromethoxy-5-methoxy-phenyl.

In certain embodiments of formula I, R¹ is 2,5-dimethoxy-phenyl.

In certain embodiments of formula I, R¹ is 2-ethyl-4,5-dimethoxy-phenyl.

In certain embodiments of formula I, R¹ is 2-methyl-5-(2-hydroxy-ethoxy)-4-chloro-phenyl.

In certain embodiments of formula I, R¹ is 2,5-dimethyl-phenyl.

In certain embodiments of formula I, R¹ is 2-bromo-5-methoxy-phenyl.

In certain embodiments of formula I, R¹ is 2-bromo-4,5-dimethyl-phenyl.

In certain embodiments of formula I, R¹ is phenyl substituted one, two or three times with a substituent or substituents each independently selected from: C₁₋₆alkyl; C₁₋₆alkoxy; halo; hydroxy-C₁₋₆alkoxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is phenyl substituted one, two or three times with a substituent or substituents each independently selected from: C₁₋₆alkyl; C₁₋₆alkoxy; halo; hydroxy-C₁₋₆alkoxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is phenyl substituted one, two or three times with a substituent or substituents each independently selected from: C₁₋₆alkyl; C₁₋₆alkoxy; halo; hydroxy-C₁₋₆alkoxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is phenyl substituted one, two or three times with a substituent or substituents each independently selected from: methyl; methoxy, chloro; bromo; 2-hydroxy-ethoxy; 5-methyl-1H-pyrazol-3-yl; 4-methyl-pyrazol-1-yl; 4,5-dimethyl-4H-[1,2,4]triazol-3-yl; 2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl; 2H-pyrazol-3-yl; 1-((R)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl; 4-((R)-2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; 6-oxo-6H-pyridazin-1-yl; 3-methyl-6-oxo-6H-pyridazin-1-yl; 6-oxo-1,6-dihydro-pyrazin-2-yl; 2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl); 4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; 1-((S)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl; 2-ethyl-3-oxo-2,3-dihydro-pyridazin-4-yl); 1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl; 6-oxo-1,6-dihydro-pyridazin-3-yl; 2-((R)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl; 2-oxo-pyrrolidin-1-yl; 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl; 3-methyl-2-oxo-2H-pyridin-1-yl; 2-oxo-2H-pyridin-1-yl; 6-methoxy-pyridazin-3-yl; or 2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl.

In certain embodiments of formula I, R¹ is phenyl substituted:

at the 2-position with: C₁₋₆alkyl; or halo;

at the 4-position with: hydrogen; C₁₋₆alkoxy; or halo; and

at the 5-position with: C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is phenyl substituted:

at the 2-position with: methyl; halo; or bromo;

at the 4-position with: hydrogen; methoxy; or chloro; and

at the 5-position with: methoxy; hydroxy-ethoxy; 5-methyl-1H-pyrazol-3-yl; 4-methyl-pyrazol-1-yl; 4,5-dimethyl-4H-[1,2,4]triazol-3-yl); 2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl; 2H-pyrazol-3-yl; 1-((R)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl; 4-((R)-2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; 6-oxo-6H-pyridazin-1-yl; 3-methyl-6-oxo-6H-pyridazin-1-yl; 6-oxo-1,6-dihydro-pyrazin-2-yl; 2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl); 4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; 1-((S)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl; 2-ethyl-3-oxo-2,3-dihydro-pyridazin-4-yl); 1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl; 6-oxo-1,6-dihydro-pyridazin-3-yl; 2-((R)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl; 2-oxo-pyrrolidin-1-yl; 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl; 3-methyl-2-oxo-2H-pyridin-1-yl; 2-oxo-2H-pyridin-1-yl; 6-methoxy-pyridazin-3-yl; or 2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl.

In certain embodiments of formula I, R¹ is optionally substituted heteroaryl.

In certain embodiments of formula I, R¹ is: quinolinyl; isoquinolinyl; qinoxalinyl; phthalizinyl; indolyl; or indazolyl; each optionally substituted once or twice with a group or groups independently selected from: C₁₋₆alkyl; halo; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; halo; and oxo.

In certain embodiments of formula I, R¹ is: quinolinyl; isoquinolinyl; phthalizinyl; indolyl; or indazolyl; each optionally substituted once or twice with a group or groups independently selected from: C₁₋₆alkyl; halo; hydroxy-C₁₋₆alkyl; halo; and oxo.

In certain embodiments of formula I, R¹ is: quinolinyl; isoquinolinyl; or indazolyl; each substituted once or twice with a group or groups independently selected from: C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; and oxo.

In certain embodiments of formula I, R¹ is: 6-methyl-quinolin-5-yl; 2,6-dimethyl-quinolin-5-yl; 6-methyl-2-oxo-1,2-dihydro-quinolin-5-yl; 5-ethyl-2-methyl-quinolin-6-yl; 1-(2-hydroxy-ethyl)-5-methyl-1H-indazol-6-yl; 1,5-dimethyl-1H-indazol-6-yl; 2-methyl-1-oxo-1,2-dihydro-isoquinolin-5-yl; or 2-methyl-1-oxo-1,2-dihydro-isoquinolin-5-yl.

In certain embodiments of formula I, R¹ is: 5-ethyl-quinolin-6-yl; 7-ethyl-quinolin-6-yl; 6-methyl-quinolin-5-yl; quinolin-5-yl; 2-methyl-quinolin-5-yl; 7-chloro-2-(2-hydroxy-1-methyl-ethyl)-1-oxo-2,3-dihydro-isoindol-4-yl; 2-oxo-6-methyl-1H-quinolin-5-yl;

In certain embodiments of formula I, R² is optionally substituted phenyl.

In certain embodiments of formula I, R² is phenyl optionally substituted one, two, three or four times with a substituent or substituents each independently selected from: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfanyl; C₁₋₆alkylsulfinyl; phenylsulfonyl wherein the phenyl portion is optionally substituted with C₁₋₆alkyl; nitrile; hydroxy; C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkoxycarbonyl; C₁₋₆alkoxycarbonyl-C₁₋₆alkoxy; hydroxycarbonyl; hydroxycarbonyl-C₁₋₆alkoxy; C₁₋₆alkylaminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylamino-C₁₋₆alkoxy; C₁₋₆alkylsulfony-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkoxy; amino; amino-C₁₋₆alkyl; C₁₋₆alkenyl; C₁₋₆alkynyl; morpholinyl; morpholinyl-C₁₋₆alkyl; piperazinyl; piperidinyloxy; aminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxyamino-C₁₋₆alkyl; hydroxy-C₁₋₆alkylamino-C₁₋₆alkyl; C₁₋₆alkoxycarbonylamino-C₁₋₆alkyl; C₁₋₆alkylcarbonylamino-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl; C₁₋₆alkoxycarbonyl-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl; C₁₋₆alkylamino-C₁₋₆alkyl; hydroxycarbonyl-C₁₋₆alkyl; or nitro; or two adjacent substituents may form a C₁₋₂alkylenedioxy or halo-C₁₋₂ alkylenedioxy.

In certain embodiments of formula I, R² is phenyl optionally substituted once or twice with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; methanesulfanyl; methanesulfinyl; toluenesulfonyl; nitrile; acetyl; aminocarbonyl; methoxycarbonyl; methoxycarbonylmethoxy; carboxy; hydroxycarbonylmethoxy; methylaminocarbonylmethoxy; methoxyethoxy; hydroxyethoxy; methylaminoethoxy; methanesulfonylpropyloxy; hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; amino; or nitro; or two adjacent substituents may form methylenedioxy, ethylenedioxy or difluoromethylenedioxy.

In certain embodiments of formula I, R² is phenyl substituted once or twice with a substituent or substituents each independently selected from: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; nitrile; alkoxyalkoxy; hydroxyalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkoxy.

In certain embodiments of formula I, R² is phenyl optionally substituted once or twice with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.

In certain embodiments of formula I, R² is phenyl substituted once or twice with a substituent or substituents each independently selected from: fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.

In certain embodiments of formula I, R² is phenyl substituted once or twice with a substituent or substituents each independently selected from: halo; methyl; methoxy; trifluoromethyl; difluoromethoxy; nitrile; or methanesulfonyl.

In certain embodiments of formula I, R² is phenyl substituted once or twice with a substituent or substituents each independently selected from: fluoro; chloro; methyl; methoxy; or nitrile.

In certain embodiments of formula I, R² is phenyl optionally substituted once or twice with halo.

In certain embodiments of formula I, R² is phenyl substituted once or twice with fluoro.

In certain embodiments of formula I, R² is: phenyl; 4-fluoro-phenyl; 3-fluoro-phenyl; 2-fluoro-phenyl; 2-chloro-phenyl; 3,4-difluoro-phenyl; 3,5-difluoro-phenyl; 3-methyl-phenyl; 4-methyl-phenyl; or 3-cyano-phenyl.

In certain embodiments of formula I, R² is: phenyl; 4-fluoro-phenyl; 3-fluoro-phenyl; 2-fluoro-phenyl; 2-chloro-phenyl; 3,4-difluoro-phenyl; or 3,5-difluoro-phenyl.

In certain embodiments of formula I, R² is 4-fluoro-phenyl or 3-fluoro-phenyl.

In certain embodiments of formula I, R² is 4-fluoro-phenyl.

In certain embodiments of formula I, R² is 3-fluoro-phenyl.

In certain embodiments of formula I, R² is 3,4-difluoro-phenyl.

In certain embodiments of formula I, R² is optionally substituted C₃₋₆cycloalkyl.

In certain embodiments of formula I, R² is C₃₋₆cycloalkyl optionally substituted with halo.

In certain embodiments of formula I, R² is cyclohexyl.

In certain embodiments of formula I, R² is cyclohexyl optionally substituted once or twice with halo.

In certain embodiments of formula I, R² is cyclohexyl optionally substituted once or twice with fluoro.

In certain embodiments of formula I, X is —O—.

In certain embodiments of formula I, X is —NR^(a)—.

In certain embodiments of formula I, X is —S(O)_(m)—.

In certain embodiments of formula I, X is —CR^(b)R^(c)—.

In certain embodiments of formula I, X is —CHR^(b)—.

In certain embodiments of formula I, X is —CH₂—.

In certain embodiments of formula I, m is 0.

In certain embodiments of formula I, m is 1.

In certain embodiments of formula I, m is 2.

In certain embodiments of formula I, R^(a) is hydrogen.

In certain embodiments of formula I, R^(a) is C₁₋₆alkyl.

In certain embodiments of formula I, R^(a) is C₁₋₆alkyl-carbonyl.

In certain embodiments of formula I, R^(a) is methyl.

In certain embodiments of formula I, R^(a) is acetyl.

In certain embodiments of formula I, R^(b) is hydrogen.

In certain embodiments of formula I, R^(b) is C₁₋₆alkyl.

In certain embodiments of formula I, Y is —O—.

In certain embodiments of formula I, Y is —NR^(d)—.

In certain embodiments of formula I, Y is —S(O)_(n)—.

In certain embodiments of formula I, Y is —CR^(d)R^(c).

In certain embodiments of formula I, R^(d) is hydrogen.

In certain embodiments of formula I, R^(d) is C₁₋₆alkyl.

In certain embodiments of formula I, R^(e) is hydrogen.

In certain embodiments of formula I, R^(e) is C₁₋₆alkyl.

In certain embodiments of formula I, R^(f) is hydrogen.

In certain embodiments of formula I, R^(f) is C₁₋₆alkyl.

In certain embodiments of formula I, n is 0.

In certain embodiments of formula I, n is 1.

In certain embodiments of formula I, n is 2.

In certain embodiments, the compounds of formula I may be more specifically of formula II:

wherein:

p is from 0 to 3;

each R⁵ independently is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; or nitrile;

R⁶, R⁷, R⁸, R⁹ and R¹⁰ each independently is: hydrogen; halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfanyl; C₁₋₆alkylsulfinyl; phenylsulfonyl wherein the phenyl portion is optionally substituted with C₁₋₆alkyl; nitrile; hydroxy; C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkoxycarbonyl; C₁₋₆alkoxycarbonyl-C₁₋₆alkoxy; hydroxycarbonyl; hydroxycarbonyl-C₁₋₆alkoxy; C₁₋₆alkylaminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylamino-C₁₋₆alkoxy; C₁₋₆alkylsulfony-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkoxy; amino; amino-C₁₋₆alkyl; C₁₋₆alkenyl; C₁₋₆alkynyl; morpholinyl; morpholinyl-C₁₋₆alkyl; piperazinyl; piperidinyloxy; aminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxyamino-C₁₋₆alkyl; hydroxy-C₁₋₆alkylamino-C₁₋₆alkyl; C₁₋₆alkoxycarbonylamino-C₁₋₆alkyl; C₁₋₆alkylcarbonylamino-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl; C₁₋₆alkoxycarbonyl-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl; C₁₋₆alkylamino-C₁₋₆alkyl; hydroxycarbonyl-C₁₋₆alkyl; or nitro; or two adjacent substituents may form a C₁₋₂alkylenedioxy; halo-C₁₋₂alkylenedioxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted;

and

X and R^(d) are as defined herein for formula I.

In certain embodiments of formula II, the subject compounds may be more specifically of formula IIa or formula IIb;

wherein X, p, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R^(d) are as defined herein.

In certain embodiments, the subject compounds are of formula IIa.

In certain embodiments, the subject compounds are of formula IIb.

In certain embodiments of any of formulas II, IIa and IIb, at least one of R⁶, R⁷, R⁸, R⁹ and R¹⁰ is not hydrogen.

In certain embodiments of any of formulas II, IIa and IIb, at least two of R⁶, R⁷, R⁸, R⁹ and R¹⁰ are not hydrogen.

In certain embodiments of any of formulas II, IIa and IIb, at least three of R⁶, R⁷, R⁸, R⁹ and R¹⁰ are not hydrogen.

In certain embodiments of any of formulas II, IIa and IIb, R⁶, R⁷, R⁸, R⁹ and R¹⁰ each independently is: hydrogen; fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; trifluoromethoxy; methanesulfonyl; methanesulfanyl; methanesulfinyl; toluenesulfonyl; nitrile; acetyl; aminocarbonyl; methoxycarbonyl; methoxycarbonylmethoxy; carboxy; hydroxycarbonylmethoxy; methylaminocarbonylmethoxy; methoxyethoxy; hydroxyethoxy; methylaminoethoxy; methanesulfonylpropyloxy; hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; amino; or nitro; morpholinyl; N,N-dimethylaminocarbonylmethoxy; boc-piperazinyl; N-(2-methoxyethyl)-N-methylaminomethyl; N,N-dimethylaminomethyl; aminomethyl; boc-aminomethyl; methylcarbonylaminomethyl; N,N-di-(2-hydroxyethyl)-aminomethyl; morpholinylmethyl; 2-hydroxy-1-hydroxymethyl-ethyl; methylaminocarbonyl; piperidinyloxy; tert-butoxycarbonylmethyl; N,N-dimethylaminocarbonylmethyl; n-propyl; isopropyl; hydroxycarbonylmethyl; hydroxypropoxy; a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted; or two adjacent substituents may form methylenedioxy, ethylenedioxy or difluoromethylenedioxy.

In certain embodiments of any of formulas II, IIa and IIb, two of R⁶, R⁷, R⁸, R⁹ and R¹⁰ are hydrogen, and the remaining ones of R⁶, R⁷, R⁸, R⁹ and R¹⁰ of each independently is: hydrogen; fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylenedioxy; or ethylenedioxy.

In certain embodiments of any of formulas II, IIa and IIb, two of R⁶, R⁷, R⁸, R⁹ and R¹⁰ are hydrogen, and the remaining ones of R⁶, R⁷, R⁸, R⁹ and R¹⁰ of each independently is: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylenedioxy; or ethylenedioxy.

In certain embodiments of any of formulas II, IIa and IIb, two of R⁶, R⁷, R⁸, R⁹ and R¹⁰ are hydrogen, and the remaining ones of R⁶, R⁷, R⁸, R⁹ and R¹⁰ of each independently is: hydrogen; fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; difluoromethoxy; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylenedioxy; or ethylenedioxy.

In certain embodiments of any of formulas II, IIa and IIb, two of R⁶, R⁷, R⁸, R⁹ and R¹⁰ are hydrogen, and the remaining ones of R⁶, R⁷, R⁸, R⁹ and R¹⁰ of each independently is: hydrogen; fluoro; chloro; bromo; methyl; and methoxy.

In certain embodiments of any of formulas II, IIa and IIb, R⁶ is halo or methyl, R¹⁰ is hydrogen, one of R⁷, R⁸ and R⁹ is hydrogen and the others of R⁷, R⁸ and R⁹ are each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; and hydroxypropoxy.

In certain embodiments of any of formulas II, IIa and IIb, R⁶ is halo or methyl, R¹⁰ is hydrogen, two of R⁷, R⁸ and R⁹ is hydrogen and the other of R⁷, R⁸ and R⁹ is selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrite; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; and hydroxypropoxy.

In certain embodiments of any of formulas II, IIa and IIb, R⁶, R⁷, R⁸, R⁹ and R¹⁰ each independently is: hydrogen; halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; nitrile; alkoxyalkoxy; hydroxyalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkoxy.

In certain embodiments of any of formulas II, IIa and IIb, R⁶, R⁷, R⁸, R⁹ and R¹⁰ each independently is: hydrogen; fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrite; methoxyethoxy; hydroxyethoxy; hydroxymethyl; or hydroxyethyl.

In certain embodiments of any of formulas II, IIa and IIb, R⁶, R⁷, R⁸, R⁹ and R¹⁰ each independently is: hydrogen; fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.

In certain embodiments of any of formulas II, IIa and IIb, R⁷ and R¹⁰ are hydrogen.

In certain embodiments of any of formulas II, IIa and IIb, R⁷, R⁸ and R¹⁰ are hydrogen.

In certain embodiments of any of formulas II, IIa and IIb, R⁶ is: hydrogen; halo; or C₁₋₆alkyl.

In certain embodiments of any of formulas II, IIa and IIb, R⁶ is: halo; or C₁₋₆alkyl.

In certain embodiments of any of formulas II, IIa and IIb, R⁶ is: halo; or methyl.

In certain embodiments of any of formulas II, IIa and IIb, R⁶ is: bromo; chloro; or methyl.

In certain embodiments of any of formulas II, IIa and IIb, R⁶ is: bromo; or methyl.

In certain embodiments of any of formulas II, IIa and IIb, R⁶ is methyl.

In certain embodiments of any of formulas II, IIa and IIb, R⁸ is hydrogen; methoxy; halo; methyl; or difluoromethoxy.

In certain embodiments of any of formulas II, IIa and IIb, R⁸ is hydrogen; methoxy; or halo.

In certain embodiments of any of formulas II, IIa and IIb, R⁸ is: hydrogen.

In certain embodiments of any of formulas II, IIa and IIb, R⁹ is: methoxy; hydrogen; 2-hydroxy-ethoxy; 2-methoxy-ethoxy; 1-hydroxy-ethyl; or cyclopropylmethyl.

In certain embodiments of any of formulas II, IIa and IIb, R⁹ is: methoxy; hydrogen; 2-hydroxy-ethoxy; 2-methoxy-ethoxy; 1-hydroxy-ethyl; cyclopropylmethyl; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas II, IIa and IIb, R⁹ is: methoxy; 2-hydroxy-ethoxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; halo; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas II, IIa and IIb, R⁹ is: methoxy; 2-hydroxy-ethoxy; or a five- or six-membered heteroaryl selected from pyrazolyl and pyridazinyl, the pyrazolyl and pyridazinyl being optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; halo; or hydroxy-C₁₋₆alkyl.

In certain embodiments of any of formulas II, IIa and IIb, R⁹ is: methoxy; 2-hydroxy-ethoxy; 5-methyl-1H-pyrazol-3-yl; 4-methyl-pyrazol-1-yl; 5-methyl-1-(2-hydroxy-ethyl)-pyrazol-3-yl; 5-methyl-1-(2-hydroxy-propyl)-pyrazol-3-yl; 5-methyl-1-(1,2-dihydroxy-propyl)-pyrazol-3-yl; 5-methyl-1-(3-methoxy-2-hydroxy-propyl)-pyrazol-3-yl; 6-oxo-1-methyl-pyridazin-5-yl; 5-methyl-1-(2-hydroxy-ethyl)-pyrazol-3-yl; 6-oxo-1H-pyridazin-3-yl; or 6-oxo-1H-pyridazin-5-yl.

In certain embodiments of any of formulas II, IIa and IIb, R⁹ is: methoxy; 2-hydroxy-ethoxy; 5-methyl-1H-pyrazol-3-yl; 4-methyl-pyrazol-1-yl; 4,5-dimethyl-4H-[1,2,4]triazol-3-yl; 2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl; 2H-pyrazol-3-yl; 1-((R)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl; 4-((R)-2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; 6-oxo-6H-pyridazin-1-yl; 3-methyl-6-oxo-6H-pyridazin-1-yl; 6-oxo-1,6-dihydro-pyrazin-2-yl; 2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl); 4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; 1-((S)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl; 2-ethyl-3-oxo-2,3-dihydro-pyridazin-4-yl); 1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl; 6-oxo-1,6-dihydro-pyridazin-3-yl; 2-((R)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl; 2-oxo-pyrrolidin-1-yl; 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl; 3-methyl-2-oxo-2H-pyridin-1-yl; 2-oxo-2H-pyridin-1-yl; 6-methoxy-pyridazin-3-yl; 2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl; or 4-((R)-2-hydroxy-3-methoxy-propyl)-2H-[1,2,4]triazine-3,5-dione]-1-yl.

In certain embodiments of any of formulas II, IIa and IIb, p is 0, 1 or 2.

In certain embodiments of any of formulas II, IIa and IIb, p is 1 or 2.

In certain embodiments of any of formulas II, IIa and IIb, p is 1.

In certain embodiments of any of formulas II, IIa and IIb, each R¹¹ independently is: halo; C₁₋₆alkyl; or C₁₋₆alkoxy.

In certain embodiments of any of formulas II, IIa and IIb, each R¹¹ independently is fluoro or methyl.

In certain embodiments of any of formulas II, IIa and IIb, R¹¹ is halo.

In certain embodiments of any of formulas II, IIa and IIb, R¹¹ is fluoro.

In certain embodiments of any of formulas II, IIa and IIb p is 1 and R¹¹ is halo.

In certain embodiments of any of formulas II, IIa and IIb p is 1 or 2 and R¹¹ is halo.

In certain embodiments of any of formulas II, IIa and IIb p is 1 and R¹¹ is 3-halo or 4-halo.

In certain embodiments of any of formulas II, IIa and IIb p is 1 and R¹¹ is fluoro.

In certain embodiments of any of formulas II, IIa and IIb p is 1 and R¹¹ is 3-fluoro or 4-fluoro.

In certain embodiments of any of formulas II, IIa and IIb p is 1 and R¹¹ is 4-fluoro.

In certain embodiments, the compounds of formula I may be more specifically of formula III:

wherein X, R⁵, R⁶, R⁸ and R⁹ are as defined herein.

In certain embodiments of formula III, the subject compounds may be more specifically of formula IIIa or formula IIIb;

wherein X, R⁵, R⁶, R⁸ and R⁹ are as defined herein.

In certain embodiments, the subject compounds are of formula IIIa.

In certain embodiments, the subject compounds are of formula IIIb.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁶ is: halo; methyl; or ethyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁶ is methyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁶ is ethyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁶ is bromo.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁸ and R⁹ each independently is: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or hydroxypropoxy.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁸ is: hydrogen; methoxy; halo; methyl; or difluoromethoxy.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁸ is: hydrogen; methoxy; or halo.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁸ is hydrogen.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁸ is methoxy.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁸ is chloro.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁸ is fluoro.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is: methoxy; 2-hydroxy-ethoxy; 2-methoxy-ethoxy; 1-hydroxy-ethyl; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is: methoxy; 2-hydroxy-ethoxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is methoxy.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is 2-hydroxy-ethoxy.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is 2-methoxy-ethoxy.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is 1-hydroxy-ethyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; or hydroxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is pyrrolyl optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is pyrazolyl optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is triazolyl optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is pyridinyl optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is pyrimidinyl optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is pyrazinyl optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is pyridazinyl optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is triazinyl, each optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is: 5-methyl-1H-pyrazol-3-yl; 4-methyl-pyrazol-1-yl; 4,5-dimethyl-4H-[1,2,4]triazol-3-yl; 2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl; 2H-pyrazol-3-yl; 1-((R)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl; 4-((R)-2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; 6-oxo-6H-pyridazin-1-yl; 3-methyl-6-oxo-6H-pyridazin-1-yl; 6-oxo-1,6-dihydro-pyrazin-2-yl; 2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl); 4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; 1-((S)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl; 2-ethyl-3-oxo-2,3-dihydro-pyridazin-4-yl); 1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl; 6-oxo-1,6-dihydro-pyridazin-3-yl; 2-((R)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl; 2-oxo-pyrrolidin-1-yl; 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl; 3-methyl-2-oxo-2H-pyridin-1-yl; 2-oxo-2H-pyridin-1-yl; 6-methoxy-pyridazin-3-yl; 2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl; or 4-((R)-2-hydroxy-3-methoxy-propyl)-2H-[1,2,4]triazine-3,5-dione]-1-yl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is: methoxy; 2-hydroxy-ethoxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; halo; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; or hydroxy-C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is: methoxy; 2-hydroxy-ethoxy; or a five- or six-membered heteroaryl selected from pyrazolyl and pyridazinyl, the pyrazolyl and pyridazinyl being optionally substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; halo; or hydroxy-C₁₋₆alkyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is: methoxy; 2-hydroxy-ethoxy; 5-methyl-1H-pyrazol-3-yl; 4-methyl-pyrazol-1-yl; 5-methyl-1-(2-hydroxy-ethyl)-pyrazol-3-yl; 5-methyl-1-(2-hydroxy-propyl)-pyrazol-3-yl; 5-methyl-1-(1,2-dihydroxy-propyl)-pyrazol-3-yl; 5-methyl-1-(3-methoxy-2-hydroxy-propyl)-pyrazol-3-yl; 6-oxo-1-methyl-pyridazin-5-yl; 5-methyl-1-(2-hydroxy-ethyl)-pyrazol-3-yl; 6-oxo-1H-pyridazin-3-yl; or 6-oxo-1H-pyridazin-5-yl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁶ is: bromo; or methyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R⁹ is: methoxy; 2-hydroxy-ethoxy; 2-methoxy-ethoxy; or 1-hydroxy-ethyl.

In certain embodiments of any of formulas III, IIIa and IIIb, R¹¹ is halo.

In certain embodiments of any of formulas III, IIIa and IIIb, R¹¹ is fluoro.

Where any of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(a), R^(b), R^(e), R^(d) or R^(e) is alkyl or contains an alkyl moiety, such alkyl is preferably lower alkyl, i.e. C₁-C₆alkyl, and in many embodiments is C₁-C₄alkyl.

The invention also provides methods for treating a disease or condition mediated by or otherwise associated with a P2X₇ receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.

The invention also provides methods for treating an inflammatory, respiratory or diabetes condition, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention together with an effective amount of a P2X7 inhibitor.

The disease may be an inflammatory disease such as arthritis, and more particularly rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, irritable bowel disease, and Crohn's disease.

The disease may be a pain condition, such as inflammatory pain; surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve injury; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.

The disease may be a respiratory disorder, such as chronic obstructive pulmonary disorder (COPD), asthma, or bronchospasm, or a gastrointestinal (GI) disorder such as Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension.

The disease may be diabetes.

Representative compounds in accordance with the methods of the invention are shown in Table 1.

TABLE 1 # Structure Name (Autonom) M + H pIC50 1

(2-Bromo-4,5-dimethoxy- phenyl)-(5-phenyl-5,6,7,8- tetrahydro- [1,2,4]triazolo[4,3- a]pyridin-3-yl)-amine 430 7.25 2

(5-Ethyl-quinolin-6-yl)-[5- (4-fluoro-phenyl)-5,6,7,8- tetrahydro- [1,2,4]triazolo[4,3- a]pyridin-3-yl]-amine 388 7.52 3

(7-Ethyl-quinolin-6-yl)-[5- (4-fluoro-phenyl)-5,6,7,8- tetrahydro- [1,2,4]triazolo[4,3- a]pyridin-3-yl]-amine 388 6.875 4

(4,5-Dimethoxy-2-methyl- phenyl)-[(S)-5-(4-fluoro- phenyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3- a]pyridin-3-yl]-amine 383 7.98 5

(2-Bromo-4,5-dimethoxy- phenyl)-[5-(4-fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-yl]-amine 450 7.775 6

2-{2-Chloro-5-[5-(4- fluoro-phenyl)-5,6,7,8- tetrahydro- [1,2,4]triazolo[4,3- a]pyridin-3-ylamino]-4- methyl-phenoxy}-ethanol 418 6.99 7

(2-Bromo-4,5-dimethoxy- phenyl)-(7,7′-spiro- ethylenedioxy-5-phenyl- 5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3- a]pyridin-3-yl)-amine 488 6.2 8

(5-Ethyl-quinolin-6-yl)- [(S)-5-(4-fluoro-phenyl)- 5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3- a]pyridin-3-yl]-amine 388 7.693 9

(5-Ethyl-quinolin-6-yl)- [(R)-5-(4-fluoro-phenyl)- 5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3- a]pyridin-3-yl]-amine 388 5.17 10

(2-Bromo-4,5-dimethoxy- phenyl)-[5-(4-fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]thiazin-3-yl]-amine 466 7.625 11

(6-Methyl-quinolin-5-yl)- ((R)-5-phenyl-5,6-dihydro- 8H-[1,2,4]triazolo[3,4- c][1,4]oxazin-3-yl)-amine 358 7.442 12

(2-Bromo-4,5-dimethoxy- phenyl)-[(S)-5-(4-fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-yl]-amine 450 5.1167 13

(2-Bromo-4,5-dimethoxy- phenyl)-[(R)-5-(4-fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-yl]-amine 450 7.75 14

[(R)-5-(4-Fluoro-phenyl)- 5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-yl]-[2- methyl-5-(5-methyl-1H- pyrazol-3-yl)-phenyl]- amine 405 7.62 15

2-{2-Chloro-5-[(S)-5-(4- fluoro-phenyl)-5,6,7,8- tetrahydro- [1,2,4]triazolo[4,3- a]pyridin-3-ylamino]-4- methyl-phenoxy}-ethanol 417 7.133 16

(2-Bromo-4,5-dimethoxy- phenyl)-[5-(4-fluoro- phenyl)-7-oxo-5,6,7,8- tetrahydro-7λ⁴- [1,2,4]triazolo[3,4- c][1,4]thiazin-3-yl]-amine 482 7.4167 17

(2-Bromo-4,5-dimethoxy- phenyl)-[5-(4-fluoro- phenyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3- a]pyrazin-3-yl]-amine 449 7.3267 18

(4,5-Dimethoxy-2-methyl- phenyl)-[5-(4-fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]thiazin-3-yl]-amine 401 7.58 19

(4,5-Dimethoxy-2-methyl- phenyl)-[5-(4-fluoro- phenyl)-7,7-dioxo-5,6,7,8- tetrahydro-7λ⁶- [1,2,4]triazolo[3,4- c][1,4]thiazin-3-yl]-amine 433 6.96 20

[5-(3-Fluoro-phenyl)-5,6- dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-yl]- quinolin-5-yl-amine 362 6.987 21

2-{2-Chloro-5-[(R)-5-(4- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenoxy}-ethanol 420 7.59 22

[(R)-5-(4-Fluoro-phenyl)- 5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-yl]-[2- methyl-5-(4-methyl- pyrazol-1-yl)-phenyl]- amine 405 7.855 23

(4,5-Dimethoxy-2-methyl- phenyl)-[5-(4-fluoro- phenyl)-5-methyl-5,6- dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-yl]-amine 399 6.9 24

1-[3-(2-Bromo-4,5- dimethoxy-phenylamino)- 5-(4-fluoro-phenyl)-5,6- dihydro-8H- [1,2,4]triazolo[4,3- a]pyrazin-7-yl]-ethanone 491 6.945 25

[5-(3-Fluoro-phenyl)-5,6- dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-yl]-(6- methyl-quinolin-5-yl)- amine 376 7.735 26

(2-Bromo-4,5-dimethoxy- phenyl)-[5-(4-fluoro- phenyl)-7-methyl-5,6,7,8- tetrahydro- [1,2,4]triazolo[4,3- a]pyrazin-3-yl]-amine 463 7.32 27

[(R)-5-(4-Fluoro-phenyl)- 5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-yl]-(2- methyl-quinolin-5-yl)- amine 376 6.76 28

7-Chloro-4-[5-(3-fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 2-((R)-2-hydroxy-1-methyl- ethyl)-2,3-dihydro-isoindol- 1-one 459 5.625 29

2-{2-Chloro-5-[5-(3- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenoxy}-ethanol 420 7.13 30

2-(3-{3-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-5- methyl-pyrazol-1-yl)- ethanol 449 7.735 31

(R)-1-(3-{3-[(R)-5-(4- Fluoro-phenyl)-5,6- dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-5- methyl-pyrazol-1-yl)- propan-2-ol 463 7.45 32

(R)-3-(3-{3-[(R)-5-(4- Fluoro-phenyl)-5,6- dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-5- methyl-pyrazol-1-yl)- propane-1,2-diol 479 7.5475 33

(R)-1-(3-{3-[(R)-5-(4- Fluoro-phenyl)-5,6- dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-5- methyl-pyrazol-1-yl)-3- methoxy-propan-2-ol 493 7.56 34

(S)-1-(3-{3-[(R)-5-(4- Fluoro-phenyl)-5,6- dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-5- methyl-pyrazol-1-yl)- propan-2-ol 463 7.4 35

(S)-3-(3-{3-[(R)-5-(4- Fluoro-phenyl)-5,6- dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-5- methyl-pyrazol-1-yl)- propane-1,2-diol 479 7.755 36

[(R)-5-(4-Fluoro-phenyl)- 5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-yl]-(6- methyl-quinolin-5-yl)- amine 376 7.87 37

4-{3-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-2- methyl-2H-pyridazin-3-one 433 7.865 38

5-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 6-methyl-1H-quinolin-2- one 392 7.46 39

2-{6-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 5-methyl-indazol-1-yl}- ethanol 409 7.605 40

2-(3-{4-Chloro-3-[(R)-5- (4-fluoro-phenyl)-5,6- dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- phenyl}-5-methyl-pyrazol- 1-yl)-ethanol 470 7.54 41

6-{3-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-2H- pyridazin-3-one 419 7.665 42

5-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 2H-phthalazin-1-one 379 6.135 43

4-{3-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-2H- pyridazin-3-one 419 8.28 44

2-{2-Chloro-5-[(R)-5-(3- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenoxy}-ethanol 420 7.6 45

2-{2-Chloro-5-[(S)-5-(3- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenoxy}-ethanol 420 46

2-{2-Chloro-5-[(R)-5-(4- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo[3,4- c][1,4]thiazin-3-ylamino]- 4-methyl-phenoxy}-ethanol 436 47

2-{2-Chloro-5-[(5R,7R)-5- (4-fluoro-phenyl)-7-oxo- 5,6,7,8-tetrahydro- 7lambda*4*- [1,2,4]triazolo[3,4- c][1,4]thiazin-3-ylamino]- 4-methyl-phenoxy}-ethanol 452 7.705 48

6-Bromo-5-[(R)-5-(4- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 2H-phthalazin-1-one 458 7.57 49

4-{4-Bromo-3-[(R)-5-(4- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- phenyl}-2H-pyridazin-3- one 484 8.2 50

2-{2-Chloro-5-[(R)-5-(4- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-2H- pyridazin-3-one 454 7.17 51

4-{3-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]thiazin-3-ylamino]- 4-methyl-phenyl}-2- methyl-2H-pyridazin-3-one 449 8.16 52

4-{3-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-2-(2- hydroxy-ethyl)-2H- pyridazin-3-one 463 8.09 53

4-{4-[(R)-5-(4-Fluoro- phenyl)-7,7-dioxo-5,6,7,8- tetrahydro-7λ⁶- [1,2,4]triazolo[3,4- c][1,4]thiazin-3-ylamino]- 3-methyl-phenyl}-2- methyl-2H-pyridazin-3-one 481 54

1-{4-Bromo-3-[(R)-5-(4- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo-[3,4- c][1,4]oxazin-3-ylamino]- phenyl}-tetrahydro- pyrimidin-2-one 488 7.325 55

4-{4-Fluoro-3-[(R)-5-(4- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- phenyl}-2-methyl-2H- pyridazin-3-one 437 8.035 56

2-{3-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-4- methyl-2H-[1,2,4]triazine- 3,5-dione 484 57

3-{3-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-1- methyl-1H-pyridin-2-one 432 58

2-{3-Fluoro-5-[(R)-5-(4- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo-[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-2H- pyridazin-3-one 437 59

2-{2-Fluoro-5-[(R)-5-(4- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-2H- pyridazin-3-one 437 60

4-Ethyl-2-{3-[(R)-5-(4- fluoro-phenyl)-5,6-dihydro- 8H-[1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-2H- [1,2,4]triazine-3,5-dione 464 61

1-{3-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-1H- pyridin-2-one 418 62

2-{3-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]oxazin-3-ylamino]- 4-methyl-phenyl}-4-((R)-2- hydroxy-3-methoxy- propyl)-2H-[1,2,4]triazine- 3,5-dione 524 63

4-{3-[(R)-5-(4-Fluoro- phenyl)-5,6-dihydro-8H- [1,2,4]triazolo[3,4- c][1,4]thiazin-3-ylamino]- 4-methyl-phenyl}-2H- pyridazin-3-one 435 64

4-{3-[(R)-5-(4-Fluoro- phenyl)-7-oxo-5,6,7,8- tetrahydro-7λ⁴- [1,2,4]triazolo[3,4- c][1,4]thiazin-3-ylamino]- 4-methyl-phenyl}-2H- pyridazin-3-one 451 65

4-{3-[(R)-5-(4-Fluoro- phenyl)-7-oxo-5,6,7,8- tetrahydro-7λ⁴- [1,2,4]triazolo[3,4- c][1,4]thiazin-3-ylamino]- 4-methyl-phenyl}-2- methyl-2H-pyridazin-3-one 465 66

4-{3-[(S)-5-(4-Fluoro- phenyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3- a]pyridin-3-ylamino]-4- methyl-phenyl}-2H- pyridazin-3-one 417 Synthesis

Compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below.

The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this application.

The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about −78° C. to about 150° C., more preferably from about 0° C. to about 125° C., and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to prepare specific compounds of formula I, wherein Z is a leaving group, and X, R¹, R² and R³ are as defined herein.

In step 1 of Scheme A, heterocyclic ketone a is treated with phosphorus pentasulfide to afford the corresponding thione compound b. In step 2 heterocyclyl thione b undergoes an S-alkylation with alkylating agent RZ to yield thio imine compound c as a salt of leaving group Z. In step 3 thio imine compound c is reacted with aryl semicarbazide compound d to afford semicarbazone compound e. Aryl semicarbazide compound d may be prepared by treatment of the corresponding arylamine with phosgene or phenyl chloroformate, followed by hydrazine, as described in the experimental examples below. In step 4, semicarbazone compound e undergoes a cyclization in the presence of dichloro-triphenylphosphine, to provide triazole compound f, which is a compound of formula I in accordance with the invention.

Many variations on the procedure of Scheme A are possible and will suggest themselves to those skilled in the art. Specific details for producing compounds of the invention are described in the Examples section below.

Utility

The compounds of the invention are usable for the treatment of a wide range of inflammatory diseases and conditions such as arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions. The subject compounds would be useful for the treatment of pulmonary disorders or lung inflammation, including adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis, and chronic pulmonary inflammatory disease.

The compounds of the invention are also expected to find utility as analgesics in the treatment of diseases and conditions associated with pain from a wide variety of causes, including, but not limited to, inflammatory pain such as pain associated with arthritis (including rheumatoid arthritis and osteoarthritis), surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injuries (including fractures and sports injuries), and pain associated with functional bowel disorders such as irritable bowel syndrome.

Further, compounds of the invention are useful for treating respiratory disorders, including chronic obstructive pulmonary disorder (COPD), asthma, bronchospasm, and the like.

Additionally, compounds of the invention are useful for treating gastrointestinal disorders, including Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension, and the like.

The compounds of the invention are also useful for the treatment of muscular sclerosis and diabetes.

Administration and Pharmaceutical Composition

The invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.

In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.

Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.

The compounds of the invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The compounds of the invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.

The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.

The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatine or blister packs from which the powder may be administered by means of an inhaler.

When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylazacycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa. Representative pharmaceutical formulations containing a compound of the present invention are described below.

EXAMPLES

The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Unless otherwise stated, all temperatures including melting points (i.e., MP) are in degrees Celsius (° C.). It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. The following abbreviations may be used in the Preparations and Examples.

ABBREVIATIONS BETBDMS 2-bromoethoxy tertbutyldimethylsilane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane/methylene chloride DIPEA diisopropyl ethylamine (Hunig's base) DME 1,2-dimethoxyethane (glyme) DMF N,N-dimethylformamide DMFDMA N,N-dimethylformamide dimethyl acetal DMSO dimethyl sulfoxide DMAP 4-dimethylaminopyridine dppf 1,1′-Bis(diphenylphosphino)ferrocene EDCI 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide EtOAc ethyl acetate EtOH ethanol gc gas chromatography HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HMPA hexamethylphosphoramide HOAc acetic acid HOBt N-Hydroxybenzotriazole hplc high performance liquid chromatography IPA isopropanol IPBAPE isopropenylboronic acid pinacol ester mCPBA m-chloroperbenzoic acid MeCN acetonitrile NMM N-methyl morpholine NMP N-methyl pyrrolidinone Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0) TBAF tetra-n-butyl ammonium fluoride tBDMSICl tert-butyl-dimethylsilyl chloride TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran LDA lithium diisopropylamine TBDMS tert-butyl dimethylsilyl chloride TLC thin layer chromatography Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene

Preparation 1 (R)-3-(4-Fluoro-phenyl)-5-[1,2,4]triazol-1-yl-3,6-dihydro-2H-[1,4]oxazine

The synthetic procedure used in this preparation is outlined in Scheme B.

Step 1 (R)-5-(4-Fluoro-phenyl)-morpholin-3-one

To a stirring mixture of NaH (1.1 g, 45.7 mmol) in THF (30 mL) at room temperature under N₂ atmosphere was added dropwise a solution of (R)-2-amino-2-(4-fluoro-phenyl)-ethanol (5.0 g, 32.2 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 30 minutes, then cooled to 0° C. A solution of ethyl chloroacetate (4.0 g, 33 mmol) in THF (30 mL) was added dropwise, and the reaction mixture was stirred for 30 minutes at 0° C., then stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue. The resulting mixture was pH adjusted to approximately 6.5 by addition of 1M aqueous HCl, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na₂SO₄), filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 2.87 g of (R)-5-(4-fluoro-phenyl)-morpholin-3-one. The mother liquor from the recrystallization was concentrated and purified via chromatography (50-70% ethyl acetate in hexanes) to give an additional 1.0 g of (R)-5-(4-fluoro-phenyl)-morpholin-3-one.

Step 2 (R)-3-(4-Fluoro-phenyl)-5-[1,2,4]triazol-1-yl-3,6-dihydro-2H-[1,4]oxazine

A solution of 20 grams (0.1025 mole) R-5-(4-fluoro-phenyl)-morpholin-3-one, 71 grams (1.03 mole), 1,2,4-triazole, and 86 mL (0.615 mole) and triethylamine in 480 mL acetonitrile was stirred and cooled in an ice-water bath. A solution of 19 mL (0.205 mole) phosphorous oxychloride in 20 mL acetonitrile was added dropwise over 20 minutes keeping the temperature under 30 degrees C. The reaction mixture was then heated under reflux for 1.5 hours. The mixture was cooled to room temperature and 35 mL (0.25 mole) triethylamine was added followed by 400 mL ethyl acetate. The mixture was filtered and concentrated under reduced pressure. The residue was partitioned between 400 mL ethyl acetate and 80 mL 10% sodium bicarbonate containing 25 mL saturated sodium chloride. The organic phase was dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was dissolved in 60 mL ethyl acetate; this solution was passed through a pad of 300 mL neutral alumina which had been slurry-packed with 50% ethyl acetate-hexane. The alumina was further eluted with 500 mL ethyl acetate. The eluate was concentrated under reduced pressure. The residue was recrystallized from ethyl ether to provide 17.84 grams of (R)-3-(4-fluoro-phenyl)-5-[1,2,4]triazol-1-yl-3,6-dihydro-2H-[1,4]oxazine, m.p. 165-167.

Preparation 2 (R)-3-(3-Fluoro-phenyl)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]oxazine

The synthetic procedure used in this preparation is outlined in Scheme C.

Step 1 (R)-5-(3-Fluoro-phenyl)-morpholin-3-one

To a stirring mixture of NaH (900 mg, 37.5 mmol) in THF (25 mL) at room temperature under N₂ atmosphere was added dropwise a solution of (R)-2-amino-2-(3-fluoro-phenyl)-ethanol (4.0 g, 26.4 mmol) in THF (25 mL). The reaction mixture was stirred at room temperature for 30 minutes, then cooled to 0° C. A solution of ethyl chloroacetate (3.31 g g, 27 mmol) in THF (10 mL) was added dropwise, and the reaction mixture was stirred for 25 minutes at 0° C., then stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 1:1 mixture of brine and water. The organic layer was separated, dried (Na₂SO₄), filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 1.73 g (34%) of (R)-5-(3-fluoro-phenyl)-morpholin-3-one, MP=119-121° C.

Step 2 (R)-5-(3-Fluoro-phenyl)-morpholine-3-thione

To a stirred room temperature suspension of P₄S₁₀ (6.0 g, 13.4 mmol) and Na₂CO₃ (1.42 g, 13.4 mmol) in THF (40 mL) was slowly added a solution of (R)-5-(3-fluoro-phenyl)-morpholin-3-one (2.16 g, 11.1 mmol) in THF (30 mL). The mixture was stirred at room temperature for two hours, and then quenched by addition of 10% aqueous Na₃PO₄ (50 mL). The mixture was stirred another five minutes and then extracted with a 1:1: mixture of ethyl acetate and diethyl ether. The organic layer was separated, dried (MgSO₄), filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel using a 15-30% ethyl acetate/hexanes solvent gradient to give 1.84 g (78%) of (R)-5-(3-fluoro-phenyl)-morpholine-3-thione as a white solid, MP=124-125° C.

Step 3 (R)-3-(3-Fluoro-phenyl)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]oxazine

To a room temperature solution of (R)-5-(3-fluoro-phenyl)-morpholine-3-thione (128 mg, 0.61 mmol) in methylene chloride (5 mL) under N₂ atmosphere was added methyl triflate (0.2 mL, 1.77 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then concentrated under reduced pressure to give crude (R)-3-(3-fluoro-phenyl)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]oxazine as a triflate salt, which was used directly without further purification.

Preparation 3 3-(4-Fluoro-phenyl)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]thiazine

The synthetic procedure used in this preparation is outlined in Scheme D.

Step 1 [1-(4-Fluoro-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester

To a stirring room temperature solution of 2-amino-2-(4-fluoro-phenyl)-ethanol (15.4 g, 99.2 mmol) in THF (150 mL) was added di-tert-butyl dicarbonate (23 g, 105 mmol) followed by TEA (14 mL, 101 mmol). The reaction mixture was stirred for two hours at room temperature, then concentrated under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate, and the organic phase was separated, washed with saturated aqueous sodium bicarbonate, dried over MgSO₄, filtered and concentrated under reduced pressure to give 25.0 g (98%) of [1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester], MP=85-86° C.

Step 2 [1-(4-Fluoro-phenyl)-2-iodo-ethyl]-carbamic acid tert-butyl ester

To a room temperature solution of triphenylphosphine dichloride (1.53 g (5.85 mmol) in methylene chloride was added iodine (1.481 g, 5.85 mmol). The mixture was stirred for fifteen minutes, then imidazole (663 mg, 9.74 mmol) was added. The mixture was stirred another 15 minutes, then [1-(4-fluoro-phenyl)-2-hydroxy-ethyl]carbamic acid tert-butyl ester (1.0 g, 3.9 mmol) was added. The mixture was heated to reflux for two hours, then stirred at room temperature overnight. Solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium thiosulfate. The organic layer was separated, washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (5-10% ethyl acetate/hexanes) to give 820 mg (58%) of [1-(4-fluoro-phenyl)-2-iodo-ethyl]-carbamic acid tert-butyl ester, MP=138-139° C.

Step 3 [2-tert-Butoxycarbonylamino-2-(4-fluoro-phenyl)-ethylsulfanyl]-acetic acid methyl ester

A mixture of [1-(4-fluoro-phenyl)-2-iodo-ethyl]-carbamic acid tert-butyl ester (3.88 g, 10.6 mmol), mercapto-acetic acid methyl ester (1.24 g, 11.7 mmol) and potassium carbonate (12.21 g, 18 mmol) in acetone (100 mL) was heated to reflux with stirring for 90 minutes. The mixture was then cooled and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, and the organic layer was separated, washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure. The residue was recrystallized from hexanes to give 3.34 g of [2-tert-Butoxycarbonylamino-2-(4-fluoro-phenyl)-ethylsulfanyl]-acetic acid methyl ester, MP=61-62° C.

Step 4 5-(4-Fluoro-phenyl)-thiomorpholin-3-one

A solution of [2-tert-butoxycarbonylamino-2-(4-fluoro-phenyl)-ethylsulfanyl]-acetic acid methyl ester (3.23 g, 9.4 mmol) in trifluoroacetic acid (10 mL) was stirred at 50° C. for 10 hours. The solution was then concentrated under reduced pressure, and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was separated, dried (Na₂SO₄), filtered and concentrated under reduced pressure to give 2.0 g of 5-(4-fluoro-phenyl)-thiomorpholin-3-one, MP=111-112° C.

Step 5 5-(4-Fluoro-phenyl)-thiomorpholine-3-thione

A mixture of phosphorus pentasulfide (5.12 g, 11.5 mmol) and sodium carbonate (1.22 g, 11.5 mmol) in THF (30 mL) was stirred at room temperature. A solution of 5-(4-fluoro-phenyl)-thiomorpholin-3-one (2.0 g, 9.5 mmol) in THF (25 mL) was slowly added, and the mixture was stirred at room temperature for 90 minutes. The mixture was diluted with 10% aqueous Na₃PO₄ solution (40 mL), and stirred at room temperature for five minutes. The mixture was extracted with a 1:4 mixture of ethyl acetate and diethyl ether, and the organic phase was separated, dried over MgSO₄, filtered and concentrated under reduced pressure. Elution of the residue through silica (15-20% ethyl acetate/hexanes) gave 1.36 g of 5-(4-fluoro-phenyl)-thiomorpholine-3-thione, MP=107-108° C.

Step 6 3-(4-Fluoro-phenyl)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]thiazine

To a room temperature solution of 5-(4-fluoro-phenyl)-thiomorpholine-3-thione (710 mg, 3.2 mmol) in THF (20 mL) was added methyl iodide (1.1 mL, 16.7 mmol). The mixture was stirred at room temperature in the dark 18 hours, then concentrated under reduced pressure to give crude 3-(4-fluoro-phenyl)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]thiazine as a hydroiodide salt, which was used directly in without further purification.

Preparation 4 [6-Phenyl-piperidin-(2Z)-ylidene]-hydrazine

The synthetic procedure used in this preparation is outlined in Scheme E.

Step 1 (3-Hydroxy-1-phenyl-propyl)-carbamic acid benzyl ester

To a stirring room temperature solution of 3-mmino-3-phenyl-propan-1-ol (36 mmol) in a mixture of EtOAc (60 mL) and aqueous sodium carbonate (70 mL of 1.5M solution) was added benzyl chloroformate (40 mmol). The reaction mixture was stirred for two hours at room temperature, and then the layers were separated. The organic layer was washed with 5% aqueous HCl, dried over MgSO₄, filtered and concentrated under reduced pressure. The resulting oil was chromatographed (10%-60% EtOAc in hexanes) to give 4.7 g (46%) of (3-hydroxy-1-phenyl-propyl)-carbamic acid benzyl ester as a colorless oil.

Step 2 (4-Oxo-1-phenyl-butyl)-carbamic acid benzyl ester

To a stirred solution of oxalyl chloride (1.6 mL, 18.2 mmol) in methylene chloride (20 mL) at −50° C. was added drop-wise a solution of DMSO (2.84 g, 36.4 mmol). The resulting mixture was stirred at −50° C. for 15 minutes, and a solution of (3-hydroxy-1-phenyl-propyl)-carbamic acid benzyl ester (4.7 g, 16.53 mmol) in methylene chloride 35 mL). The mixture was stirred at −50° C. for 15 minutes, then TEA (11.5 mL, 82.7 mmol) was added. The mixture was stirred for five minutes at −50° C., then allowed to stir at room temperature for 30 minutes. The reaction mixture was washed with 5% aqueous HCl, dried over MgSO₄, filtered and concentrated under reduced pressure to give 4.7 g (100%) of (4-oxo-1-phenyl-butyl)-carbamic acid benzyl ester as a pale yellow oil.

Step 3 4-Benzyloxycarbonylamino-4-phenyl-butyric acid methyl ester

To a stirring room temperature suspension of LiCl (0.84 g, 19.8 mmol) in dry acetonitrile (50 mL) was added trimethyl phosphonoacetate (4 mL, 24.75 mmol). The resulting mixture was stirred for 5 minutes, then TEA (2.76 mL, 19.8 mmol) was added. The reaction mixture was stirred for 10 minutes, and then a solution of (4-oxo-1-phenyl-butyl)-carbamic acid benzyl ester (16.5 mmol) in acetonitrile (15 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, then diluted with diethyl ether and saturated aqueous NH₄Cl. The organic layer was separated, washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to an oil, which was chromatographed (5%-40% EtOAc in hexanes) to give 4.41 g (79%) of 4-benzyloxycarbonylamino-4-phenyl-butyric acid methyl ester as a colorless oil.

Step 4 6-Phenyl-piperidin-2-one

4-Benzyloxycarbonylamino-4-phenyl-butyric acid methyl ester was dissolved in EtOH (30 mL), and 10% palladium on activated carbon (1.1 g) was added. The mixture was stirred under hydrogen atmosphere at 45 psi (3.1 bar) for 22 hours at room temperature and 4 hours at 65° C. The mixture was filtered and the filtrated was concentrated under reduced pressure. The residue was recrystallized from a mixture of methanol, diethyl ether and hexanes to give 1.85 g (81%) of 6-phenyl-piperidin-2-one as colorless crystals.

Step 5 [6-Phenyl-piperidin-(2Z)-ylidene]-hydrazine

To a stirring solution of 6-phenyl-piperidin-2-one (0.35 g, 2 mmol) in methylene chloride (1 mL) at 0° C. under nitrogen atmosphere was added methyl triflate (0.23 mL, 2 mmol). The reaction mixture was stirred at room temperature for three hours, then added to a stirring 0°C solution of anhydrous hydrazine (0.5 mL) in methanol (1 mL). The mixture was stirred for 3.5 hours at room temperature, then poured into a 1:1 mixture of methylene chloride and diethyl ether. The mixture was washed with 1.5M aqueous sodium carbonate, dried over anhydrous potassium carbonate, filtered, and concentrated under reduced pressure to give 0.34 g (90%) of [6-phenyl-piperidin-(2Z)-ylidene]-hydrazine as a colorless oil.

Similarly prepared was [6-(4-fluoro-phenyl)-piperidin-(2Z)-ylidene]-hydrazine.

Preparation 5 [6-(4-Fluoro-phenyl)-1H-pyrazin-(2Z)-ylidene]-hydrazine

The synthetic procedure used in this preparation is outlined in Scheme F.

Step 1 2-Chloro-6-(4-fluoro-phenyl)-pyrazine

A mixture of 2,6-dichloropyrazine (2.75 g, 18.3 mmol), 4-fluorophenyl boronic acid (2.3 g, 16.5 mmol) and palladium tetrakis triphenylphosphine (0.1 g) in dioxane (50 mL) was stirred at 60° C. for one hour. The mixture was cooled and partitioned between water and diethyl ether. The organic layer was separated, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether and methanol to give 1.2 g of 2-chloro-6-(4-fluoro-phenyl)-pyrazine.

Step 2 [6-(4-Fluoro-phenyl)-1H-pyrazin-(2Z)-ylidene]-hydrazine

A mixture of 2-chloro-6-(4-fluoro-phenyl)-pyrazine (1.0 g, 4.7 mmol) and anhydrous hydrazine (1.5 mL, 47 mmol) in dioxane (20 mL) was heated to reflux for two hours, then cooled and diluted with cold water. The resulting precipitate was collected by filtration, washed with cold water, and dried to give 0.85 g of [6-(4-fluoro-phenyl)-1H-pyrazin-(2Z)-ylidene]-hydrazine.

Preparation 6 5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine semicarbazide

The synthetic procedure used in this preparation is outlined in Scheme G.

Step 1 5-Amino-2-chloro-phenol

To a solution of 2-chloro-5-nitrophenol (20.0 g, 115.2 mmol) in ethanol (150 ml) and water (150 ml) was added iron powder (32.2 g, 576.2 mmol) and ammonium chloride (32.1 g, 599.3 mmol). The mixture was heated at reflux for two hours, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/9:1) gave 5-amino-2-chloro-phenol (15.85 g, 96%) as a white solid.

Step 2 5-Amino-4-bromo-2-chloro-phenol

To a solution of 5-amino-2-chloro-phenol (15.85 g, 110.4 mmol) in dichloromethane (300 ml) and MeOH (150 ml) was added tetrabutylammonium tribromide (58.6 g, 121.4 mmol). The mixture was stirred at room temperature for 20 minutes, and then was partitioned between saturated aqueous Na₂SO₃ and Et₂O. The organic layer was separated, washed with water and brine, dried over MgSO₄, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/7:3) gave 5-amino-4-bromo-2-chloro-phenol (4.38 g, 18%) as a white solid.

Step 3 2-Bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-phenylamine

To a solution of 5-amino-4-bromo-2-chloro-phenol (0.338 g, 1.52 mmol) in NMP (5 ml) was added cesium carbonate (0.644 g, 1.97 mmol), sodium iodide (0.228 g, 1.52 mmol) and 2-bromoethoxy tertbutyldimethylsilane (0.424 g, 1.97 mmol). The mixture was heated to 100° C. for two hours, then cooled to room temperature. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO₄, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/8:2) gave 2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-phenylamine (0.505 g, 78%) as a white solid.

Step 4 5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine

To a solution of 2-bromo-4-chloro-5 (2-dimethyl-tert-butylsiloxyethyl)-oxy aniline (6.5 g, 17.07 mmol) in Dioxane (120 ml)-Water (12 ml) under Ar atmosphere was added potassium carbonate (7.08 g, 51.2 mmol), trimethylboroxine (2.408 ml, 17.07 mmol) and PdCl₂(dppf)-CH₂Cl₂ (1.394 g, 1.707 mmol). The mixture was heated to 110° C. for 20 hours, then cooled to room temperature and filtered through Celite. Water and EtOAc were added, and the organic layer was separated, washed with water and brine, dried (Na₂SO₄), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (0 to 20% EtOAc in hexanes to give 3.66 g of 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine as a white solid. Recrystallization from EtOAc gave 2.35 g of white crystals.

Step 5 5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine semicarbazide

Phosgene (6 mL of 2M solution in toluene, 12 mmol) was diluted with diethyl ether (75 mL), and the mixture was stirred at 0° C. To the stirring solution was added drop-wise a solution of 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine (3.0 g, 9.5 mmol) and TEA (4 mL, 28.6 mmol) in diethyl ether (60 mL). The mixture was stirred at 0° C. for 15 minutes, and then filtered directly into a stirring room temperature solution of anhydrous hydrazine (98%) in EtOH (50 mL). The mixture was stirred at room temperature for 20 minutes, then concentrated under reduced pressure. The residue was partitioned between water and EtOAc and water, and the organic phase was separated, washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to give 3.4 g (96%) of 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine semicarbazide as a white solid, MP=136-137° C.

Preparation 7 1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine Semicarbazide

The synthetic procedure used in this preparation is outlined in Scheme H.

Step 1 5-Methyl-6-nitro-1H-indazole

2,4-Dimethyl-5-nitroaniline (1.662 g, 10.00 mmol) was dissolved in glacial acetic acid (100 ml) and the mixture was cooled to 0° C. A solution of sodium nitrite (1 eq, 690 mg) in water (2 ml) was added while maintaining a temperature below 25° C. Stirring was continued for three hours and the mixture was filtered. The filtrate was allowed to stand for three days at room temperature, then was concentrate under reduced pressure. The residue was diluted with water and the resulting mixture was stirred vigorously. The solid product was collected by filtration, washed thoroughly with cold water, and dried. The product was purified by flash chromatography (99:1 dichloromethane/methanol) to give 1.030 g (58.1%) of 5-methyl-6-nitro-1H-indazole as a solid.

Step 2 1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-1H-indazole

5-Methyl-6-nitro-1H-indazole (354 mg, 2.0 mmol) was dissolved in DMF (10 ml) and the mixture was cooled to 0° C. with stirring. Lithium hexamethyldisilazane (2.2 ml of 1.0 M toluene solution) was added dropwise. The mixture was allowed to stir for five minutes, and then (2-bromoethoxy)-tert-butyldimethylsilane (0.52 ml, 2.4 mmol) was added. The mixture was stirred for 30 minutes at 0° C., then allowed to warm to room temperature with stirring for four hours. The reaction was quenched with pH2 buffer solution, and the mixture was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 4:1 hexanes/ethyl acetate) to give 340 mg (50.7%) of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-1H-indazole as a white powder.

Step 3 1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine

1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-1H-indazole (335 mg, 100 mmol) was dissolved in 30 ml of a 1:1 mixture of ethanol and water. To this mixture was added ammonium chloride (108 mg) and iron powder (108 mg). The mixture was then stirred at reflux for two hours, then was cooled and filtered. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (95:5 dichloromethane/methanol) to give 240 mg (78.7%) of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine as a tan solid.

Step 4 1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine Semicarbazide

A stirring solution of phosgene (0.5 mL of 2M toluene solution) in diethyl ether (5 mL) was cooled to 0° C. To this stirring solution was added drop-wise a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine (150 mg, 0.49 mmol) and TEA (0.5 mL, 3.57 mmol) in diethyl ether (10 mL). The mixture was stirred for 10 minutes at 0° C., and then filtered directly into a stirring room temperature solution of anhydrous hydrazine (9%) in EtOH (5 mL). The reaction mixture was stirred for ten minutes, then concentrated to reduced pressure. The residue was partitioned between water and EtOAc and water, and the organic phase was separated, washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to give 150 mg of 1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine semicarbazide.

Preparation 8 2-Bromo-4,5-dimethoxy-aniline Semicarbazide

The synthetic procedure used in this preparation is outlined in Scheme I.

Step 1 2-Bromo-4,5-dimethoxy-aniline

Following the procedure reported in JACS 1996, 118, 1028-1030, 4-aminoveratrole (3.06 g, 20.0 mmol) was dissolved in a mixture of dichloromethane (80 ml) and methanol (40 ml) at room temperature. Tetrabutylammonium tribromide (1.15 eq, 11.09 g) was added and the mixture was allowed to stir for 20 minutes. The mixture was extracted with saturated aqueous sodium sulfite solution. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 10:1 to 7:3 hexanes/ethyl acetate) to give 2-bromo-4,5-dimethoxy-aniline 1.403 g (30%) of a yellow oil.

Step 2 2-Bromo-4,5-dimethoxy-aniline Semicarbazide

Following the procedure of step 4 of Preparation 7,2-bromo-4,5-dimethoxy-aniline was treated with phosgene, followed by hydrazine, to afford 2-bromo-4,5-dimethoxy-aniline semicarbazide.

Preparation 9 6-Amino-5-ethylquinoline Semicarbazide

The synthetic procedure used in this preparation is outlined in Scheme J.

Step 1 6-Amino-5-ethylquinoline

To a mixture of 183 mg (0.22 mmol) of Pd(dppf)Cl₂.CH₂Cl₂ and 4.38 g (13.44 mmol) of Cs₂CO₃ in 13 mL of DMF under Argon atmosphere was added a solution of 500 mg (2.24 mmol) of 6-amino-5-bromoquinoline (commercially available from ACES Pharma Product List). Triethylborane in hexanes (2.91 mL of 1.0 M solution) was added, and the reaction was heated to 50° C. for 22 hours, then poured into 50 mL of water, and extracted with diethyl ether. The combined ether layers were washed with saturated aqueous NaHCO₃ solution and brine, dried over MgSO₄, filtered, and concentrated under reduced pressure to an oil. The oil was purified via silica gel chromatography, eluting with 0 to 50% EtOAc/hexanes to give 386 mg (65.8%) of 6-amino-5-ethylquinoline as e a colorless oil. MS (ESI): m/z 173.2 (M+H)⁺.

Step 2 6-Amino-5-ethylquinoline Semicarbazide

6-Amino-5-ethylquinoline semicarbazide was prepared by treatment of 6-amino-5-ethylquinoline with phosgene, followed by hydrazine as described above in Preparation 7, to afford 2-bromo-4,5-dimethoxy-aniline semicarbazide.

Preparation 10 2-Methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine Semicarbazide

The synthetic procedure used in this preparation is outlined in Scheme K.

Step 1 5-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole

A solution of 1-(4-methyl-3-nitro-phenyl)-ethanone and (1,1-dimethoxy-ethyl)-dimethyl-amine in DMF was heated at 90° C. for 3 hours, then cooled to room temperature. Solvent was removed under reduced pressure, and the residue was dissolved in a mixture of EtOH (25 ml) and THF (5 ml). The mixture was cooled to 0° C., and hydrazine hydrate (5 ml) at 0° C. was added. The mixture was stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue was purified by “flash chromatography” (0 to 30% EtOAc in hexanes) to give 8.5 g of 5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole as a yellowish solid, which was recrystallyzed from EtOAc to give 8.2 g of yellow powder.

Step 2 2-Methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine

5-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole (8.2 g) was dissolved in ethanol and Palladium (10%) on activated carbon was added. The mixture was subject to barometric hydrogenation under balloon pressure for five hours at room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 414 mg of crude 2-methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine as a white solid, which was used directly without further purification.

Step 3 2-Methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine Semicarbazide

2-Methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine semicarbazide was prepared from 2-methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine using the procedure of step 4 of Preparation 7 above.

Preparation 11 5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenylamine Semicarbazide

The synthetic procedure used in this preparation is outlined in Scheme L.

Step 1 1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole

A solution of 5-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole, 2-bromoethoxy tertbutyldimethylsilane, Cs₂CO₃ and NaI in NMP was heated in a microwave oven at 100° C. for 1 hour, and then cooled to room temperature. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by “flash chromatography” (0 to 30% EtOAc in hexanes to give 867 mg of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole as an oil that also contained 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-methyl-5-(4-methyl-3-nitro-phenyl)-1H-pyrazole as a minor product.

Step 2 5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenylamine

1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole (867 mg) was dissolved in ethanol and Palladium (10%) on activated carbon was added. The mixture was subject to barometric hydrogenation under balloon pressure for five hours at room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenylamine as a white solid, which was used directly without further purification.

Step 3 5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenylamine Semicarbazide

5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenylamine was converted to the corresponding semicarbazide by treatment with phosgene followed by hydrazine, as described above in step 4 of preparation 7.

Preparation 12 (S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (2-bromo-4,5-dimethoxy-phenyl)-amide

The synthetic procedure used in this example is outlined in Scheme M.

Step 1 2-Bromo-4,5-dimethoxy-aniline

Following the procedure reported in JACS 1996, 118, 1028-1030, 4-aminoveratrole (3.06 g, 20.0 mmol) was dissolved in a mixture of dichloromethane (80 ml) and methanol (40 ml) at room temperature. Tetrabutylammonium tribromide (1.15 eq, 11.09 g) was added and the mixture was allowed to stir for 20 minutes. The mixture was extracted with saturated aqueous sodium sulfite solution. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 10:1 to 7:3 Hexanes/Ethyl Acetate) to give 2-bromo-4,5-dimethoxy-aniline 1.403 g (30%) of a yellow oil.

Step 2 1-Bromo-2-isocyanato-4,5-dimethoxy-benzene

2-Bromo-4,5-dimethoxyaniline (464 mg, 2.0 mmol) was dissolved in 10 ml of toluene at room temperature. DMAP (1 eq, 245 mg), and pyridine (1.3 eq, 0.22 ml) were added followed by phosgene (1.33 eq, 1.33 ml of a 20% solution in toluene). The mixture was heated to 90° C. for 4 hours. Upon cooling, the mixture was filtered and the filtrate was concentrated in vacuo to give 1-bromo-2-isocyanato-4,5-dimethoxy-benzene (542 mg, quantitative) as a light brown oil.

Example 1 2-{2-Chloro-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}-ethanol

The synthetic procedure used in this preparation is outlined in Scheme N.

Step 1 (R)-5-(4-Fluoro-phenyl)-morpholin-3-yl-{5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine}semicarbazone

A mixture of 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine semicarbazide (1.0 g, 2.7 mmol) and (R)-3-(4-Fluoro-phenyl)-5-[1,2,4]triazol-1-yl-3,6-dihydro-2H-[1,4]oxazine (1.31 g, 5.3 mmol) in THF (25 mL) was stirred at room temperature for one hour. Solvent was removed under reduced pressure and the residue was chromatographed through silica (35-50% EtOAc/hexanes) to give 1.15 g (77%) of (R)-5-(4-fluoro-phenyl)-morpholin-3-yl-{5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine}semicarbazone.

Step 2 {5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenyl}-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine

A mixture of (R)-5-(4-fluoro-phenyl)-morpholin-3-yl-{5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine}semicarbazone (1.0 g, 1.8 mmol), TEA (1.5 mL, 10.72 mmol) and dichloro-triphenylphosphine (1.33 g, 4 mmol) in acetonitrile (30 mL) was heated to reflux for 30 minutes, then cooled and concentrated under reduced pressure. The residue was chromatographed through silica (50-100% EtOAc/hexanes) to give 790 mg (82%) of {5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenyl}-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine, MP=141-142° C.

Step 3 2-{2-Chloro-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}-ethanol

To a stirring room temperature solution of {5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenyl}-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine (700 mg, 1.31 mmol) in MeOH (20 mL) was added 6N aqueous HCl (1.5 mL). The mixture was stirred at room temperature for 10 minutes and then concentrated to dryness under reduced pressure. The residue was partitioned between saturated aqueous sodium carbonate and EtOAc. The organic layer was separated, washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (MeOH/CH₂Cl₂/NH₄OH 5%/74.75%/0.25%) to give 520 mg (95%) of 2-{2-Chloro-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}-ethanol, MP=161-162° C., MS (M+H)=420.

Additional compounds prepared using the above procedure are shown in Table 1.

Example 2 [(R)-5-(3-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-quinolin-5-yl-amine

The synthetic procedure used in this preparation is outlined in Scheme O.

Step 1 5-(3-Fluoro-phenyl)-morpholin-3-yl-(5-amino-quinoline) semicarbazone

To a stirring room temperature solution of (R)-3-(3-fluoro-phenyl)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]oxazine triflate (approximately 230 mg, 0.6 mmol, from Preparation 2) in THF (3 mL) was added 5-amino-quinoline semicarbazide (140 mg, 0.7 mmol, prepared from commercially available (Aldrich A79205) 5-amino-quinoline). The reaction mixture was stirred for 5.5 hours at room temperature, then concentrated under reduced pressure. The residue was partitioned between saturated aqueous sodium carbonate and ethyl acetate, and the organic phase was separated, dried (MgSO₄), filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (3% MeOH in CHCl₃) to give 150 mg of 5-(3-fluoro-phenyl)-morpholin-3-yl-(5-amino-quinoline) semicarbazone as a white solid.

Step 2 [(R)-5-(3-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-quinolin-5-yl-amine

To a stirring room temperature mixture of 5-(3-fluoro-phenyl)-morpholin-3-yl-(5-amino-quinoline) semicarbazone (150 mg, 0.4 mmol) and TEA (0.3 mL, 2 mmol) in acetonitrile (15 mL) was added dichloro-triphenylphosphine (290 mg, 0.87 mmol). The mixture was heated to reflux for two hours, then additional TEA (0.2 mL, 1.43 mmol) and dichloro-triphenylphosphine (150 mg, 0.45 mmol) were added. The mixture was refluxed for another hour, then cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, and the organic layer was separated, washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (5% MeOH in chloroform) to give 78.6 mg of [(R)-5-(3-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-quinolin-5-yl-amine as a foam, MS (M+H)=362.

Additional compounds prepared using the above procedure are shown in Table 1.

Example 3 2-{6-R-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c]1.4 oxazin-3-ylamino-5-methyl-indazol-1-yl}-ethanol

The synthetic procedure used in this preparation is outlined in Scheme P.

Step 1 (R)-5-(4-Fluoro-phenyl)-morpholin-3-yl-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine}semicarbazone

A solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine semicarbazide (150 mg, 0.42 mmol) and (R)-3-(4-fluoro-phenyl)-5-[1,2,4]triazol-1-yl-3,6-dihydro-2H-[1,4]oxazine (150 mg, 0.61 mmol) in THF (5 mL) was stirred at room temperature for one hour. (R)-3-(4-Fluoro-phenyl)-5-[1,2,4]triazol-1-yl-3,6-dihydro-2H-[1,4]oxazine (25 mg, 0.1 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Solvent was removed under reduced pressure and the residue was chromatographed through silica gel (35-50% EtOAc/hexanes) to give 120 mg (53%) of (R)-5-(4-fluoro-phenyl)-morpholin-3-yl-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine}semicarbazone.

Step 2 {1-[2-tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-yl}-[(R-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine

A mixture of (R)-5-(4-fluoro-phenyl)-morpholin-3-yl-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine}semicarbazone (120 mg, 0.22 mmol), TEA (0.25 mL, 1.79 mmol) and dichloro-triphenylphosphine (180 mg, 0.54 mmol) in acetonitrile (3 mL) was heated to reflux for 20 minutes, then cooled and concentrated under reduced pressure. The residue was chromatographed through silica gel, eluting with 3% MeOH in chloroform, to give 110 mg (96%) of {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-yl}-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine

Step 3 2-{6-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-5-methyl-indazol-1-yl}-ethanol

To a stirring room temperature solution of {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-yl}-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine (110 mg, 0.21 mmol) in MeOH (5 mL) was added 6N aqueous HCl (0.5 mL). The mixture was stirred at room temperature for 15 minutes and then concentrated under reduced pressure. The residue was recrystallized from MeOH/EtOAc/diethyl ether to give 70 mg of 2-{6-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-5-methyl-indazol-1-yl}-ethanol, MP=215-217° C., MS (M+H)=409.

Additional compounds prepared using the above procedure are shown in Table 1.

Example 4 (4,5-Dimethoxy-2-methyl-phenyl)-[5-(4-fluoro-phenyl)-7,7-dioxo-5,6,7,8-tetrahydro-7lambda*6*-[1,2,4]triazolo[3,4-c][1,4]thiazin-3-yl]amine

The synthetic procedure used in this preparation is outlined in Scheme Q.

Step 1 5-(4-Fluoro-phenyl)-thiomorpholin-3-yl-(4,5-dimethoxy-2-methyl-phenylamine) semicarbazone

To a stirring room temperature solution of 3-(4-fluoro-phenyl)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]thiazine hydroiodide (3.12 mmol) in dry THF (30 mL) was added 4,5-dimethoxy-2-methyl-phenylamine semicarbazide (710 mg, 3.15 mmol). The reaction mixture was stirred at room temperature for 2 hours, then diluted with EtOAc and washed with saturated aqueous sodium carbonate. The organic layer was separated, dried (MgSO₄), filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel eulting with 20% MeOH in chloroform to give 860 mg (66%) of 5-(4-fluoro-phenyl)-thiomorpholin-3-yl-(4,5-dimethoxy-2-methyl-phenylamine) semicarbazone as a white solid, MP=161-162° C.

Step 2 (4,5-Dimethoxy-2-methyl-phenyl)-[5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]thiazin-3-yl]amine

A solution of 5-(4-fluoro-phenyl)-thiomorpholin-3-yl-(4,5-dimethoxy-2-methyl-phenylamine) semicarbazone (100 mg, 0.24 mmol), dichloro-triphenyl phosphine (177 mg, 0.53 mmol) and TEA (0.15 mL) in acetonitrile (6 mL) was stirred at 85° C. under N₂ atmosphere for 30 minutes. The solution was cooled and concentrated under reduced pressure. The residue was chromatographed through silica gel (2% MeOH in chloroform) to give 73 mg of (4,5-dimethoxy-2-methyl-phenyl)-[5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]thiazin-3-yl]-amine as a tan solid, MP=165-166° C., MS (M+H)=401.

Step 3 (4,5-Dimethoxy-2-methyl-phenyl)-[5-(4-fluoro-phenyl)-7,7-dioxo-5,6,7,8-tetrahydro-7lambda*6*-[1,2,4]triazolo[3,4-c][1,4]thiazin-3-yl]-amine

To a mixture of (4,5-dimethoxy-2-methyl-phenyl)-[5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]thiazin-3-yl]-amine (60 mg, 0.15 mmol) and 95% formic acid (1.0 mL) was added hydrogen peroxide (0.1 mL of 30% aqueous solution). The mixture was stirred for one hour at room temperature, then hydrogen peroxide (0.1 mL of 30% aqueous solution) was added. The mixture was stirred for another hour, then concentrated under reduced pressure. The residue was partitioned between water and 10% aqueous sodium carbonate solution. The organic layer was separated, dried (MgSO₄), filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (4% MeOH in chloroform) to give 34 mg (52%) of (4,5-dimethoxy-2-methyl-phenyl)-[5-(4-fluoro-phenyl)-7,7-dioxo-5,6,7,8-tetrahydro-7lambda*6*-[1,2,4]triazolo[3,4-c][1,4]thiazin-3-yl]-amine as a tan solid, MP=226-227° C., MS (M+H)=433.

Example 5 (2-Bromo-4,5-dimethoxy-phenyl)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-amine

The synthetic procedure used in this preparation is outlined in Scheme R.

Step 1 [6-Phenyl-piperidin-(2Z)-ylidene]-2-bromo-4,5-dimethoxy-phenyl semicarbazone

To a stirring solution of [6-phenyl-piperidin-(2Z)-ylidene]-hydrazine (0.34 g, 1.8 mmol) in dry THF (8 mL) was added 1-bromo-2-isocyanato-4,5-dimethoxy-benzene (0.52 g, 2 mmol). The reaction mixture was stirred at room temperature for 18 hours, then concentrated under reduced pressure. The residue was chromatographed (2% methanol in chloroform) gave 0.43 g (48%) of [6-phenyl-piperidin-(2Z)-ylidene]-2-bromo-4,5-dimethoxy-phenyl semicarbazone as a colorless foam.

Step 2 (2-Bromo-4,5-dimethoxy-phenyl)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-amine

To a stirring mixture of [6-phenyl-piperidin-(2Z)-ylidene]-2-bromo-4,5-dimethoxy-phenyl semicarbazone (0.2 g, 0.45 mmol) in 1,2-dibromo-tetrachloroethane (0.16 g, 0.5 mmol) at 0° C. was added tributyl phosphine (0.25 mL, 1 mmol), followed by TEA (0.56 mL, 2 mmol). The reaction mixture was stirred at room temperature for 90 minutes, then concentrated under reduced pressure. The residue was chromatographed (hexanes (25-50%)/in EtOAc) to give a colorless gum. Recrystallization from diethyl ether and ethyl acetate gave 28 mg of (2-bromo-4,5-dimethoxy-phenyl)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-amine as a white crystalline solid, MS (M+H)=430.

Additional compounds made by the above procedure are shown in Table 1.

Example 6 (2-Bromo-4,5-dimethoxy-phenyl)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine

The synthetic procedure used in this preparation is outlined in Scheme S.

Step 1 [6-(4-Fluoro-phenyl)-1H-pyrazin-(2Z)-ylidene]-2-bromo-4,5-dimethoxy-phenyl semicarbazone

A mixture of [6-(4-fluoro-phenyl)-1H-pyrazin-(2Z)-ylidene]-hydrazine (0.85 g, 4.2 mmol) and 1-bromo-2-isocyanato-4,5-dimethoxy-benzene (1.0 g, 4.2 mmol) in THF (40 mL) was stirred at room temperature for one hour, then concentrated under reduced pressure. The residue was recrystallized from EtOAc/hexanes to give 1.7 g of [6-(4-fluoro-phenyl)-1H-pyrazin-(2Z)-ylidene]-2-bromo-4,5-dimethoxy-phenyl semicarbazone.

Step 2 (2-Bromo-4,5-dimethoxy-phenyl)-(5-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine

[6-(4-Fluoro-phenyl)-1H-pyrazin-(2Z)-ylidene]-2-bromo-4,5-dimethoxy-phenyl semicarbazone (1.7 g, 3.7 mmol), 1,2-dibromo-tetrachloroethane (1.3 g, 4 mmol), and tributyl phosphine (2.1 mL, 8.1 mmol) were added to a mixture of acetonitrile (35 mL), dichloromethane (35 mL), THF (40 mL) and TEA (2.1 mL) under nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at room temperature, then quenched by addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc, and the combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was recrystallized from EtOAc to give 1.1 g of (2-bromo-4,5-dimethoxy-phenyl)-(5-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine.

Step 3 (2-Bromo-4,5-dimethoxy-phenyl)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine

To a stirring suspension of (2-bromo-4,5-dimethoxy-phenyl)-(5-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine (0.2 g, 3.7 mmol) in a mixture of THF (20 mL) and TFA (1 mL) at 0° C. was added sodium borohydride (20 mg, 4.0 mmol). The reaction mixture was stirred 15 minutes at room temperature, thane quenched by addition of 10% aqueous HCl. The resulting mixture was heated to reflux for 10 minutes, then cooled and made basic by addition of 1M aqueous NaOH. The mixture was extracted with EtOAc, and the combined organic layers were dried (MgSO₄), filtered and concentrated under reduced pressure to give 0.18 g of (2-bromo-4,5-dimethoxy-phenyl)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine, MS (M+H)=431.

Example 7 Formulations

Pharmaceutical preparations for delivery by various routes are formulated as shown in the following Tables. “Active ingredient” or “Active compound” as used in the Tables means one or more of the Compounds of Formula I.

Composition for Oral Administration Ingredient % wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesium stearate 0.5%

The ingredients are mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration Ingredient % wt./wt. Active ingredient 20.0% Magnesium stearate 0.5% Crosscarmellose sodium 2.0% Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0%

The ingredients are combined and granulated using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine.

Composition for Oral Administration Ingredient Amount Active compound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.5 mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation Ingredient % wt./wt. Active ingredient 0.25 g Sodium Chloride qs to make isotonic Water for injection 100 ml

The active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation Ingredient % wt./wt. Active ingredient 1.0% Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.

Topical Formulation Ingredients Grams Active compound 0.2-2 Span 60 2 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about 60° C. with stirring. A sufficient quantity of water at about 60° C. is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percent active compound are prepared as nasal spray formulations. The formulations optionally contain inactive ingredients such as, for example, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid may be added to adjust pH. The nasal spray formulations may be delivered via a nasal spray metered pump typically delivering about 50-100 microliters of formulation per actuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 8 Intracellular Calcium Flux (FLIPR) Assay

Compound and Reagent Preparation

Stock solutions of compounds were prepared from powders as a 10 mM DMSO stock solution. These solutions were stored at RT during the two week period of these experiments to prevent freeze-thaw of the DMSO stocks. The DMSO stocks were added to the appropriate assay buffer at a concentration of 10 μM, and then diluted serially to the final concentrations that were tested. No observable precipitate was formed at any time during this process. The aqueous solutions of compounds as well as ATP (Sigma A7699) and BzATP (Sigma B6396) were prepared fresh for each day of experiment.

Cell Culture: 1321N1-hP2X₇ and HEK293-rP2X₇

1321N1 cells stably expressing the full length human P2X₇ gene (1321N1-hP2X₇) and HEK293 cells stably expressing the full length rat P2X₇ gene (HEK293-rP2X₇) were obtained from the Roche Cell Culture Facility. 1321N1-hP2X₇ cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) high glucose supplemented with 10% FBS and 250 mg/mL G418. HEK293-rP2X₇ cells were grown in DMEM/F-12 supplemented with 10% FBS, 1 mM CaCl₂, 2 mM MgCl₂, 2 mM L-Glutamine and 500 mg/ml G418. Cells were split such that they never became >70% confluent.

Intracellular Calcium Flux (FLIPR)

On the day prior to the experiment, 1321N1-hP2X₇ or HEK293-rP2X₇ cells were released into suspension with calcium-free PBS+Versene and washed by centrifugation with calcium-free PBS to remove the Versene. Cells were resuspended in growth medium at a density of 2.5×10⁵ cells/mL and seeded into black walled, clear bottom 96 well plates (50,000 cells/well) approximately 18 hr prior to intracellular calcium flux experiments.

On the day of the experiment, plates were washed with FLIPR buffer (calcium- and magnesium-free Hank's Balanced Salt Solution (HBSS) supplemented with 10 mM Hepes, 2.5 mM probenecid and 2 mM calcium chloride) using a BIO-TEK 96 channel plate washer and incubated with 2 mM fluo-3 dye at 37° C. for one hr. The dye was then removed by plate washing and the cells were allowed to equilibrate for 20 min at room temperature with antagonist or vehicle (FLIPR buffer). Agonist (100 μM BzATP final concentration for hP2X₇; 5 μM BzATP final concentration or rP2X₇) was added online with the FLIPR and fluorescence measurements made at 1 sec intervals for 60 sec followed by 3 sec intervals for a further 4 min (5 min total). A final addition of 5 μM ionomycin was made and the maximal BzATP-evoked fluorescence normalized to the maximal ionomycin-evoked fluorescence.

Example 9 Human Whole Blood IL-1β Release Assay

Compound & Reagent Preparation

10 mM stock solutions of compounds in DMSO (Sigma D2650) were prepared and used either fresh or after storage at −20° C. Appropriate (200×) serial dilutions of the compounds were made in DMSO, then freshly diluted 1 to 20 (10×) with Dulbecco's phosphate buffered saline (DPBS; Mediatech Inc., 21-030), such that final DMSO concentration in the blood always equaled 0.5%.

30 mM ATP (Sigma A7699) was prepared immediately before use in 50 mM HEPES (Gibco 15630) and the pH adjusted to 7.2 with 1M sodium hydroxide.

Blood Donors

Human blood donors were medication free and restricted from utilizing alcohol or caffeine for at least the 24 hr preceding collection. The blood was collected into sodium heparin vacutainer tubes and used the same day.

Assay Method

The OptEIA Human IL-1β ELISA Set, OptEIA Coating Buffer, Assay Diluent and TMB Substrate Reagent Set used in the assay were commercially obtained from BD Pharmingen. Blood was diluted 1:1 with Dulbecco's PBS, LPS (Escherichia Coli 0127:B8, Sigma L3129) added to a final concentration of 25 ng/mL and incubated for 2 hr at 37° C. 48 μL of this LPS primed blood was added to 6 L of the 10× compound in 5% DMSO/PBS in the appropriate well of a 96-well polypropylene plate. The blood and compound were mixed and allowed to incubate for 30 min at 37° C. 6.1 of 30 mM ATP was added to the LPS-primed blood+compound, mixed thoroughly and incubated for a further 30 min at 37° C. 96 L of ELISA assay buffer was added to each well and the plate centrifuged at 4° C. 1,200 rpm for 10 min. Supernatant was removed and assayed for IL-1 using the OptiEIA kit according to the manufacturer's protocol (Serum may be frozen at −^(˜)° C. prior to assay). IC₅₀s were calculated using XLfit.

Example 10 In Vivo Assay for Asthma and Lung Function

BALb/cJ mice are immunized with a standard immunization protocol. Briefly, mice (N=8/group) are immunized i.p. with ovalbumin (OVA; 10 mg) in alum on days 0 and 14. Mice are then challenged with aerosolized OVA (5%) on day 21 and 22. Animals receive vehicle (p.o.) or a compound of the invention (100 mg/kg p.o.) all starting on day 20.

Lung function is evaluated on day 23 using the Buxco system to measure PenH in response to an aerosol methacholine challenge. Mice are then euthanized and plasma samples collected at the end of the study.

While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. 

What is claimed is:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is: phenyl substituted one, two three or four times, with a substituent or substituents each independently selected from: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfanyl; C₁₋₆alkylsulfinyl; phenylsulfonyl wherein the phenyl portion may be substituted with: C₁₋₆alkyl; nitrile; hydroxy; C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkoxycarbonyl; C₁₋₆alkoxycarbonyl-C₁₋₆alkoxy; hydroxycarbonyl; hydroxycarbonyl-C₁₋₆alkoxy; C₁₋₆alkylaminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylamino-C₁₋₆alkoxy; C₁₋₆alkylsulfony-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkoxy; amino; amino-C₁₋₆alkyl; C₁₋₆alkenyl; C₁₋₆alkynyl; morpholinyl; morpholinyl-C₁₋₆alkyl; piperazinyl; piperidinyloxy; aminocarbonyl-C₁₋₆alkoxy; hydroxy C₁₋₆alkoxy-C₁₋₆alkyl; C₁₋₆alkoxyamino-C₁₋₆alkyl; hydroxy-C₁₋₆alkylamino-C₁₋₆alkyl; C₁₋₆alkoxycarbonylamino-C₁₋₆alkyl; C₁₋₆alkylcarbonylamino-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl; C₁₋₆alkoxycarbonyl-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl; C₁₋₆alkylamino-C₁₋₆alkyl; hydroxycarbonyl-C₁₋₆alkyl; or nitro; or a five or six membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each of which may be substituted once or twice with a group or groups independently selected from: C₁₋₆alkyl; halo; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; halo; and oxo; or two adjacent substituents may form a C₁₋₂alkylenedioxy or halo-C₁₋₂alkylenedioxy; R² is phenyl substituted once or twice with a substituent or substituents each independently selected from: fluoro; chloro; methyl; methoxy; or nitrile; R³ is: hydrogen; or C₁₋₆alkyl; X is: —O; and Y is: —O—; —NR^(d)—; —S(O)_(n)— or —CR^(e)R^(f)— wherein n is 0, 1 or 2, wherein R^(d), R^(e) and R^(f) each independently is hydrogen or C₁₋₆alkyl.
 2. The compound of claim 1, wherein Y is —NR^(d)—.
 3. The compound of claim 2, wherein R^(d) is hydrogen.
 4. The compound of claim 1, wherein R³ is hydrogen.
 5. The compound of claim 1, wherein R² is phenyl substituted once or twice with fluoro.
 6. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable carrier; and (b) a compound of claim
 1. 7. A compound of formula II:

and wherein: p is 0, 1, 2or 3; each R⁵ independently is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; or nitrile; R⁶, R⁷, R⁸, R⁹ and R¹⁰ each independently is: hydrogen; halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfanyl; C₁₋₆alkylsulfinyl; phenylsulfonyl wherein the phenyl portion is optionally substituted with C₁₋₆alkyl; nitrile; hydroxy; C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkoxycarbonyl; C₁₋₆alkoxycarbonyl-C₁₋₆alkoxy; hydroxycarbonyl; hydroxycarbonyl-C₁₋₆alkoxy; C₁₋₆alkylaminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylamino-C₁₋₆alkoxy; C₁₋₆alkylsulfony-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkoxy; amino; amino-C₁₋₆alkyl; C₁₋₆alkenyl; C₁₋₆alkynyl; morpholinyl; morpholinyl-C₁₋₆alkyl; piperazinyl; piperidinyloxy; aminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxyamino-C₁₋₆alkyl; hydroxy-C₁₋₆alkylamino-C₁₋₆alkyl; C₁₋₆alkoxycarbonylamino-C₁₋₆alkyl; C₁₋₆alkyl carbonylamino-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl; C₁₋₆alkoxycarbonyl-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl; C₁₋₆alkylamino-C₁₋₆alkyl; hydroxycarbonyl-C₁₋₆alkyl; or nitro; or two adjacent substituents may form a C₁₋₂alkylenedioxy; halo-C₁₋₂alkylenedioxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each of which may be substituted once or twice with a group or groups independently selected from: C₁₋₆alkyl; halo; C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; halo; and oxo; X is: —O; and R^(d) is hydrogen or C₁₋₆alkyl.
 8. The compound of claim 7, wherein p is 1 or 2 and R⁵ is halo.
 9. The compound of claim 8, wherein R⁷ and R¹⁰ are hydrogen.
 10. The compound of claim 9, wherein R⁶ is: halo; or methyl.
 11. The compound of claim 10, wherein R⁸ is: hydrogen; methoxy; or halo.
 12. The compound of claim 11, wherein R⁹ is: methoxy; 2-hydroxy-ethoxy; or a five- or six-membered heteroaryl selected from pyrazolyl and pyridazinyl, the pyrazolyl and pyridazinyl, each of which may be substituted one, two or three times with a group or groups independently selected from: oxo; C₁₋₆alkyl; halo; or hydroxy-C₁₋₆alkyl.
 13. The compound of claim 7, wherein said compound is of formula III:


14. A compound selected from: (2-Bromo-4,5-dimethoxy-phenyl)-[5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine; (6-Methyl-quinolin-5-yl)-((R)-5-phenyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)-amine; (2-Bromo-4,5-dimethoxy-phenyl)-[(S)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine; (2-Bromo-4,5-dimethoxy-phenyl)-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine; [(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-[2-methyl-5-(5-methyl-1H-pyrazol-3-yl)-phenyl]-amine; [5-(3-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-quinolin-5-yl-amine; 2-{2-Chloro-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}-ethanol; [(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-[2-methyl-5-(4-methyl-pyrazol-1-yl)-phenyl]-amine; (4,5-Dimethoxy-2-methyl-phenyl)-[5-(4-fluoro-phenyl)-5-methyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine; [5-(3-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-(6-methyl-quinolin-5-yl)-amine; [(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-(2-methyl-quinolin-5-yl)-amine; 7-Chloro-4-[5-(3-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-2-((R)-2-hydroxy-1-methyl-ethyl)-2,3-dihydro-isoindol-1-one; 2-{2-Chloro-5-[5-(3-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}-ethanol; 2-(3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-5-methyl-pyrazol-1-yl)-ethanol; (R)-1-(3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-5-methyl-pyrazol-1-yl)-propan-2-ol; (R)-3-(3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-5-methyl-pyrazol-1-yl)-propane-1,2-diol; (R)-1-(3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-5-methyl-pyrazol-1-yl)-3-methoxy-propan-2-ol; (S)-1-(3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-5-methyl-pyrazol-1-yl)-propan-2-ol; (S)-3-(3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-5-methyl-pyrazol-1-yl)-propane-1,2-diol; [(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-(6-methyl-quinolin-5-yl)-amine; 4-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2-methyl-2H-pyridazin-3-one; 5-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-6-methyl-1H-quinolin-2-one; 2-{6-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-5-methyl-indazol-1-yl}-ethanol; 2-(3-{4-Chloro-3-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-phenyl}-5-methyl-pyrazol-1-yl)-ethanol; 6-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2H-pyridazin-3-one; 5-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-2H-phthalazin-1-one; 4-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2H-pyridazin-3-one; 2-{2-Chloro-5-[(R)-5-(3-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}-ethanol; 2-{2-Chloro-5-[(S)-5-(3-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}-ethanol; 6-Bromo-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-2H-phthalazin-1-one; 4-{4-Bromo-3-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-phenyl}-2H-pyridazin-3-one; 2-{2-Chloro-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2H-pyridazin-3-one; 4-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2-(2-hydroxy-ethyl)-2H-pyridazin-3-one; 1-{4-Bromo-3-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-phenyl}-tetrahydro-pyrimidin-2-one; 4-{4-Fluoro-3-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-phenyl}-2-methyl-2H-pyridazin-3-one; 2-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione; 3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-1-methyl-1H-pyridin-2-one; 2-{3-Fluoro-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2H-pyridazin-3-one; 2-{2-Fluoro-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2H-pyridazin-3-one; 4-Ethyl-2-{3-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2H-[1,2,4]triazine-3,5-dione; 1-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-1H-pyridin-2-one; and 2-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-4-((R)-2-hydroxy-3-methoxy-propyl)-2H-[1,2,4]triazine-3,5-dione. 